WO2003064999A2 - Methods for identifying modulators of receptor tyrosine kinases - Google Patents

Abstract

Screening methods for identifying small molecules capable of binding to the juxtamembrane-kinase interaction (JKI) site of the tyrosine kinase domain of the insulin receptor (IRK) to prevent or lessen constitutive inhibition of kinase activity. More generally, the invention relates to screening methods for identifying small molecules capable of binding to the JKI site of a tyrosine kinase domain, to modulate kinase activity in a receptor molecule comprising a JKI site.

Description

METHODS FOR IDENTIFYING MODULATORS OF RECEPTOR TYROSINE

KINASES

[0001] The research leading to the present invention was funded in part by MH/NTDDK Grant No. R01 DK52916. The Government may have certain rights in the invention.

BACKGROUND OF THE INVENTION Field of the Invention

[0003] The present invention relates to methods for designing ligands capable of binding to the tyrosine kinase domain of the insulin receptor (IRK) to prevent or lessen constitutive inhibition of kinase activity. Further, the invention relates to screening methods for identifying small molecules capable of binding to the site of the tyrosine kinase domain defined below, to prevent or lessen constitutive inhibition of kinase activity.

Statement of Related Art

[0004] Diabetes mellitus is the world's most common metabolic disorder, affecting approximately 175 million people worldwide (International Diabetes Institute, World Health

Organization), and its prevalence in the populations of developed countries is increasing at an alarming rate. The underlying causes of type II or non-insulin-dependent diabetes mellitus

(NTDDM), representing 90% of diabetes mellitus patients, are complex and involve both environmental and genetic factors. Patients with NIDDM show resistance to the metabolic actions of insulin in liver, muscle and adipose tissues. In the late stages of the disease, patients develop defects in insulin secretion from the β-cells of the pancreas.

[0005] Over the last decade, great progress has been made in deciphering the molecular signaling pathways stimulated by insulin. From these fundamental studies, several proteins have emerged as attractive targets for therapeutic intervention in NIDDM. One such target is the insulin receptor (TR) itself, for which a small molecule intracellular activator has recently been identified which significantly lowers glucose levels in diabetic mouse models (Zhang et al.

(1999) Science 284:974-977). Targets for inhibition include serine/threonine kinases such as protein kinase C and MAP kinase, whose activity desensitizes insulin signaling pathways, and the tyrosine phosphatases PTP1B and LAR, which directly dephosphorylate the IR.

[0006] The IR is an α₂β₂ transmembrane glycoprotein with intrinsic protein tyrosine kinase activity. Insulin binding to the extracellular domains of the receptor induces a conformational change in the cytopU ic domains that results in autophosphorylati of specific tyrosine residues. Tyrosine autophosphorylation stimulates the intrinsic catalytic activity of the IR and creates recruitment sites for downstream signaling proteins.

[0007] The IR is a member of the receptor tyrosine kinase (RTK) family of cell surface receptors. Because many RTKs are receptors for growth factors, overexpression of or gain-of- function mutations in RTKs contribute to the onset or progression of various types of human cancer. A large effort has been directed towards developing therapeutic agents, generally either small molecules or antibodies, to inhibit tyrosine kinase function (Levitzki (1999) Pharmacol. Ther. 82:231-239; Al-Obeidi et al. (2000) Oncogene 19:5690-5701).

SUMMARY OF THE INVENTION [0008] The tyrosine kinase domain of the insulin receptor (LRK) is subject to several autoinhibitory mechanisms to maintain a low basal state of activity. A comparison of the crystal structure of IRK in the phosphorylated, active state (Hubbard (1997) EMBO J. 16:5572-5581) and the unphosphorylated, low activity state, has revealed a site on the three-dimensional surface of IRK, termed the juxtamembrane-kinase interaction (JKI) site, which is responsible in part for suppressing the activity of the insulin receptor.

[0009] Provided herein is experimental evidence pertaining to mutant insulin receptors which shows that disruption of interactions mediated by the JKI site leads to partial activation of the receptor. The discovery of the JKI site may, therefore, be used to advantage to design small molecule ligands capable of binding specifically to the JKI site, the binding of which modulates the activity of the insulin receptor. As used herein, modulate may refer to either increasing or decreasing the activity of an insulin receptor. With regard to increasing the activity of an insulin receptor, small molecule ligands may be designed which are capable of binding specifically to the JKI site, the binding of which partially or fully activates the insulin receptor in the absence of insulin and/or sensitizes the insulin receptor in the presence of insulin. Small molecule ligands so identified effectuate a decrease in the intrinsic inhibition of the insulin receptor. Small molecule ligands which bind to and increase the activity of the insulin receptor may be referred to herein as activators of the insulin receptor. A small molecule ligand identified as an insulin receptor activator may be of utility as a therapeutic agent for the treatment of patients with type II diabetes. With regard to decreasing the activity of an insulin receptor, small molecule ligands may be designed which are capable of binding specifically to the JKI site, the binding of which partially or fully inhibits the insulin receptor in the presence of insulin or prevents subsequent activation of the insulin receptor when exposed to insulin. Small molecules which bind to and decrease the activity he insulin receptor may be referred jQ,.,herei], inhibitqrs of t suiin

P L. Ii IJ ' ι I ..:;:!! ,.^■■' D id! .1. ' 'J id! receptor. A small molecule ligand identified as an insulin receptor inhibitor may be of utility as a therapeutic agent for the treatment of patients with disorders related to aging processes.

[0010] Accordingly, in a first aspect, the invention features a method for identifying agents capable of binding with high affinity to the JKI site to modulate the activity of an insulin receptor. Such methods comprise computer docking of a test agent to the three-dimensional JKI site, and determining if the test compound binds to the JKI. The JKI site comprises a specific site on the three-dimensional structure of the insulin receptor in its native conformation, which site is formed by the underlined amino acids shown in Fig. 5 (SEQ ID NO: 1) . The binding of such agents may either increase the activity (activate) or decrease the activity (repress) of an insulin receptor. Thus, in one aspect, agents capable of binding with high affinity to the JKI site to increase the activity of an insulin receptor may be identified using the methods of the present invention. In accordance with the methods of the invention, the test agent may be a peptide- based molecule or a non-peptide based molecule.

[0011] In one embodiment, the JKI site comprises the underlined amino acids in Fig. 5. Fig. 5 shows the sequence for the juxtamembrane region and tyrosine kinase domain (SEQ LO NO:l) which spans amino acids from position 953 to 1283 of the insulin receptor (SEQ ID NO:2). In more specific embodiments, the JKI site is present as part of an intact insulin receptor (SEQ ID

NO:2) or a functional fragment thereof, or a recombinant insulin receptor or functional fragment thereof.

[0012] In one embodiment, the determination of binding of the test agent to the JKI is by in vitro assay in a cell-free system (as described below). In another embodiment, the determination of binding of the test agent to the JKI is by in vitro assay in a cell-based system (as described below).

[0013] In another embodiment, binding of the test agent to the JKI site results in a decrease in the constitutive inhibition of the insulin receptor due to the disruption of interactions between the

JKI site of the receptor and the kinase domain, specifically, between Tyr984 in the juxtamembrane region and Glu990, Leul045, Lysl052, and Nall065 in the kinase domain.

[0014] In a second aspect, the invention features a method for identifying small molecule modulators of insulin receptor activity, comprising contacting the three-dimensional JKI site with a test agent, and determining if the test agent, which in one embodiment, may be a compound, binds the JKI.

[0015] In a third aspect, the invention features a method of designing small molecules capable of binding with high affinity to the JKI site of the insulin receptor, comprising designing a test molecule to fit the JKI binding site, generating the test molecule, contacting a test molecule with the three-dimensionE 1 site, and determining if the test compoun* hds JKI. In one

IP || ^'"; ^'"!!'" ,'^■" || ⁱ[ ^ll;a!£l "^;;;ιi .^■■" If ^"|| ii"^'" "II "'"Ii r¹' embodiment, the JKI binding site is provided by the coordinate's of APPENDIX A. '" ' ""'

[0016] In a fourth aspect, the invention features a method of screening for agents capable of binding to the JKI site to modulate kinase activity, comprising contacting a JKI site with a test agent, and determining if the test agent is capable of specifically binding to the JKI site. The screening method may be a cell-based or a cell-free assay system, hi specific embodiments, the test agent is contacted with a JKI site contained in a native or recombinant insulin receptor. In another embodiment, the test agent is contacted with a functional fragment of the insulin receptor containing the JKI site. In more specific embodiments, the screening method of the invention identifies a competitive inhibitor that reduces binding of the JKI site of the insulin receptor molecule. Such competitive inhibitors serve to relieve, in part, the regulatory signals mediated through the JKI site that result in inhibition of insulin receptor activity. Accordingly, competitive inhibitors identified by the methods of the invention may be used to advantage to prevent or lessen constitutive inhibition of the insulin receptor, thereby increasing the activity of the insulin receptor.

[0017] In a specific embodiment, the invention features a method of screening for agents which modulate IR kinase activity. The screemng methods of the invention may, therefore, be used to identify agents that reduce or inhibit IRK activity. Alternatively, the screening methods of the invention may be used to advantage to identify agents that activate or decrease the constitutive inhibition of the IRK domain.

[0018] In a fifth aspect, the invention features a method of increasing the tyrosine kinase activity of an insulin receptor, comprising administering an agent capable of increasing the activity of the tyrosine kinase domain of an insulin receptor. In more specific embodiments, the agent is a molecule identified by a screening method of the invention. Such molecules include, but are not limited to a protein, a peptide, DNA, RNA, carbohydrates, lipids, peptidomimetics, and small molecules. Also encompassed are nucleic acid sequences encoding a protein or peptide activator of the tyrosine kinase domain identified using the methods of the invention. In another embodiment, the agent may be an antisense sequence or catalytic RNA capable of interfering with the expression of a natural inhibitor of the tyrosine kinase activity of an insulin receptor.

[0019] In a sixth aspect, the invention provides an antigenic peptide comprising the JKI site as shown in Fig. 5 (SEQ ID NO:l). The antigenic peptide of the invention is useful for generating antibodies specific for the JKI site of an insulin receptor, which are capable of acting as antagonists for the endogenous ligand interaction. Such inhibitory antibodies may be used to relieve the constitutive inhibition of tyrosine kinase activity mediated by this interaction. [0020] Accordingly! a related seventh aspect, the invention prov antibodies to the JKI

P C T/ ϋ iD θ 3 / O H i 9 S site of an insulin receptor which are capable of decreasing or inhibiting constitutive inhibition of tyrosine kinase activity of an insulin receptor. The antibodies of the invention specific for the JKI site include polyclonal, monoclonal, humanized, chimeric, synthetic/recombinant, and bispecific antibodies capable of immunospecific binding to the JKI site of an insulin receptor. As used herein, antibody or antibody molecule contemplates both an intact immunoglobulin molecule and an immunologically active portion of an immunoglobulin molecule such as those portions known in the art as Fab, Fab', F(ab')2 and F(v). The antibodies of the invention may be used for a variety of purposes, including, but not limited to, their use as potential therapeutics.

[0021] In an eighth aspect, agents identified using the methods of the invention are provided.

As described herein, such agents bind to the JKI site of the insulin receptor and thereby modulate the activity of the insulin receptor. Agents identified using the methods of the present invention may also be used to advantage to modulate the activity of other tyrosine kinases, including, for example, other RTKs. Specifically, RTKs comprising a site analogous or structurally similar to that of the JKI site defined herein may be bound by JKI binding agents. Such interactions may modulate (i.e., activate or inhibit) the activity of these RTKs in a manner comparable to that described herein for modulation of the insulin receptor. As described, exemplary RTKs comprising sites analogous to that of the JKI site of the insulin receptor include, but are not limited to, the vascular endothelial growth factor receptor-2

(NEGFR2) and the fibroblast growth factor receptor-1 (FGFR1). Accordingly, agents identified using the methods of the invention may be used to advantage, either alone or in a pharmaceutically acceptable composition, to modulate the activity of RTKs involved in a variety of disorders as described hereinbelow. Also featured is the use of agents identified by the methods of the invention to modulate the activity of RTKs for the treatment of various disorders. The use of agents identified that effectuate an increase in the activity of either

NEGFR2 or FGFR1 for the treatment of wounds and/or to promote vascularization is encompassed. In one aspect, the promotion of vascularization in transplanted organs or grafts is envisioned. Also provided is the use of agents identified that effectuate a decrease in the activity of either VEGFR2 or FGFR1 for the treatment of cancer and/or to inhibit tumor angiogenesis. In a particular aspect, the use of agents identified that effectuate a decrease in the activity of FGFR1 for the treatment of a craniofacial disorder, such as Crouzon Syndrome or Apert Syndrome is encompassed.

[0022] In a ninth aspect, the invention features a method for treating a patient with type II diabetes, comprising administering an agent capable of decreasing the constitutive inhibition of tyrosine kinase ac y of the insulin receptor. In more specific έ odiments, the agent is

P C T/ U S D 3 U E l ^fI B a molecule identified by a screening method of the invention, such as, for example, a peptide or a nucleic acid encoding a peptide or protein molecule capable of decreasing the constitutive inhibition of the tyrosine kinase activity of the insulin receptor. Also featured is the use of an agent identified by a screening method of the invention for the treatment type II diabetes. The use of a modulator identified by a screening method of the invention for the treatment type II diabetes is also provided. Also encompassed is the use of a nucleic acid sequence encoding such an agent for the treatment of type II diabetes. In some applications, such nucleic acid sequences may be present in an expression vector. The use of an antibody of the present invention or compositions thereof for the treatment of type II diabetes is also provided.

[0023] In a tenth aspect, the invention features a method for treating a patient with type II diabetes, comprising administering an agent capable of activating the tyrosine kinase activity of the insulin receptor. In more specific embodiments, the agent is an antisense sequence or catalytic RNA capable of interfering with the expression of a natural inhibitor of the tyrosine kinase activity of an insulin receptor. Also provided is the use of a nucleic acid sequence such as an antisense or catalytic RNA sequence for the treatment of type II diabetes.

[0024] In an eleventh aspect, the invention features a pharmaceutical composition comprised of an agent identified by a screening method of the invention and a pharmaceutically acceptable carrier. In specific embodiments, the pharmaceutical composition includes an agent which binds to the JKI site to prevent or reduce constitutive inhibition of kinase activity, a vector comprising- a nucleic acid sequence encoding a protein or peptide capable of binding to the JKI site to prevent or reduce constitutive inhibition of kinase activity, or an antisense sequence or catalytic

RNA capable of interfering with the expression of a constitutive inhibitor of the kinase activity of an insulin receptor. In further embodiments, the pharmaceutical composition includes a combination of one or more of the agents identified using the methods of the present invention.

[0025] Other features and advantages of the invention will be apparent from the detailed description, the drawings, and the claims.

BRIEF DESCRIPTION OF THE FIGURES

[0026] Fig. 1 is a schematic diagram of the human IR and location of the major tyrosine autophosphorylation sites.

[0027] Figs. 2-4 are model drawings showing the rearrangement of the JM region of the IRK upon autophosphorylation. The amino-terminal lobe of IRK is shown in molecular surface representation. Surfaces with high convex/concave curvature are colored green/dark gray. Fig. 2: Y984 in the JM re¹, i (orange) occupies the JKI site in the unph^ lorylated (pre-activated)

P C T . ^" II S O 3 ,'"^' life .1. ^ifii Eϊ kinase. Fig. 3: In phosphorylated IRK, movement of α-helix C disengages the JM region from the JKI site (red-dashed oval). Fig. 4: Side chains of residues that line the JKI site in Fig. 3 are shown explicitly.

[0028] Fig. 5 is the amino acid sequence (SEQ ID NO:l) of the juxtamembrane region and tyrosine kinase domain, wherein the underlined amino acids form the JKI site.

DETAILED DESCRIPTION

[0029] Before the present assay and treatment methodology are described, it is to be understood that this invention is not limited to particular assay methods, or test compounds and experimental conditions described, as such methods and compounds may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only the appended claims.

[0030] As used in this specification and the appended claims, the singular forms "a", "an", and "the" include plural references unless the context clearly dictates otherwise. Thus for example, references to "the method" includes one or more methods, and/or steps of the type described herein and or which will become apparent to those persons skilled in the art upon reading this disclosure and so forth.

[0031] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are now described. All publications cited are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited.

Definitions

[0032] As used herein, the term "JKI site" is the juxtamembrane-kinase interaction (JKI) site which is involved in maintaining the tyrosine kinase domain of the insulin receptor (IRK) in a state characterized by a low constitutive level of activity. As described herein, the three- dimensional structure of the JKI site is formed by the underlined amino acids shown in Fig. 5 (SEQ ID NO:l). The JKI site exists in its native three-dimensional conformation as part of the native insulin receptor and recombinant forms of the insulin receptor. As used in the methodology of the invention, the JKI site may be present as an isolated peptide fragment, as an artificial molecule having the three-dimensional structure of JKI in its native state, or as part of a larger molecule, e.g. ;ombinant insulin receptor or fragment the¹ E^". APPENDIX A,

PCT J i JS O .l 'πϊE attached hereto and incorporated by reference in its entirety into this application, shows the three-dimensional coordinates of residues 981-1283 of the insulin receptor in its phosphorylated form.

[0033] As used herein, a "functional fragment thereof refers to a part or portion of a molecule which exhibits some or all of the activities of the full length molecule.

General Description

[0034] The present invention relies in part, on the identification of a specific site on the three- dimensional surface of the tyrosine kinase domain of the IR, referred to as the juxtamembrane- kinase interaction (JKI) site. The JKI site is in the amino-terminal lobe of the kinase domain between α-helix C and the β-sheet. Previous work (Hubbard (1997) EMBO J. 16:5572-5581, herein specifically incorporated by reference in its entirety) determined the crystal structure of the phosphorylated, activated form of the IRK in complex with a peptide substrate and an ATP analog at 1.9 A resolution. The activation loop (A-loop) of the kinase undergoes a major conformational change upon autophosphorylation of tyrosine residues 1158, 1162, and 1163 (Y1158, Y1162, Yl 163) within the loop, resulting in unrestricted access of ATP and protein substrates to the kinase active site. Phosphorylated Yl 163 (pYl 163) is the key phosphotyrosine

1 in stabilizing the conformation of the tris-phosphorylated A-loop.

[0035] The hormone insulin activates signaling pathways that regulate cellular metabolism and growth. The actions of this essential hormone are mediated by the IR, a transmembrane glycoprotein located in the plasma membrane. The LR belongs to a large family of transmembrane receptors, known as receptor tyrosine kinases (RTKs), which contain intrinsic tyrosine kinase activity in the cytoplasmic domain. These receptors catalyze the transfer of the γ- phosphate of adenosine tri-phosphate (ATP) to the side chains of acceptor tyrosine residues in protein substrates. The RTK family includes, among others, the receptors for insulin-like growth factor 1 (IGF1), epidermal growth factor (EGF), the fϊbroblast growth factors (FGFs), platelet- derived growth factor (PDGF), and vascular endothelial growth factor (NEGF). There is also a large family of non-receptor tyrosine kinases which includes Src, Abl, the Janus kinases (Jaks), and Syk/Zap70. Receptor and non-receptor tyrosine kinases are critical components of signaling pathways involved in the control of cellular proliferation, differentiation, migration and metabolism.

[0036] hi contrast with most of the other members of the RTK family, which are monomeric and activated by ligand-induced oligomerization, the IR (and the related IGF1 receptor) is an α β₂ heterotetramer (Fig. 1), processed from a single-chain precursor, with disulfide linkages between the two extracellular! hains and between the -chains and the tra embrane β-chains. The r-^B C T . . 03 ^, α S .l. ^l,3l Ξ α-chains contain the binding site for insulin and consist of two so-called L domains separated by a cysteine-rich domain. These three domains are followed by the N-terminal portion of a fibronectin type III domain, the C-terminal portion of which is found in the beginning of the β- chain. A second fibronectin type III domain follows on the β-chain before a membrane-spanning helix. The cytoplasmic portion of the β-chain consists of the juxtamembrane region, the tyrosine kinase domain, and a C-terminal tail.

[0037] In the initial signal transduction event, insulin binding induces a poorly characterized structural rearrangement within the quaternary structure of the IR that results in autophosphorylation of specific tyrosines in the β-chain: two in the juxtamembrane region

(Y965/972), three in the tyrosine kinase domain (Yl 158/1162/1163), and two in the C-terminal tail (Y1328/1334) (See, for example, Kohanski (1993) Biochemistry 32:5773-5780). Most data are consistent with activation occurring by a tr ras-autophosphorylation mechanism in which the tyrosine kinase domain of one β-chain phosphorylates tyrosines on the other β-chain within the same heterotetramer. The phosphorylated tyrosines either stimulate catalytic activity

(pYl 158/1162/1163) or serve as recruitment sites for downstream signaling proteins (e.g. pY972). Both phosphotyrosine functions, stimulation of catalytic activity and recruitment, are critical in the LR activation process.

[0038] One of the mechanisms by which the tyrosine kinase domain of the IR (IRK) is subject tc autoinhibition has now been discovered to involve the juxtamembrane (JM) region, the region between the transmembrane helix and the tyrosine kinase domain. In the unphosphorylated state of the receptor, the JM region interacts with the kinase domain to partially repress kinase activity.

[0039] The experimental results described below reveal that in the unphosphorylated form of the kinase, the JKI site is masked by a tyrosine residue in the JM region, Y984 (Fig. 2), which is conserved in all IR family members. Upon autophosphorylation of the three tyrosine residues in the A-loop of the kinase, α-helix C pivots towards the carboxy-terminal domain of the kinase, displacing Y984 and the JM region from the JKI site (Fig. 3). The side chains of residues that line the JKI site of Fig. 3 are shown explicitly in Fig. 4.

General Methods

[0040] In one embodiment of the invention, the three-dimensional structural information of IRK (Hubbard (1997) supra) at the JKI site is used as a target in a virtual ligand screening procedure that seeks to identify, via computer docking methods, candidate agents, such as compounds, from a vast comport^ brary which bind with high affinity to the ti t site.

P C T/ ϋ β 03 O Ξ I ^fJ S [0041] In another embodiment, the structural information of the JKI site is used to design such agents or compounds predicted to bind to the JKI site, and such agents or compounds are tested for high affinity binding.

[0042] Compounds derived or obtained from either approach scoring the highest in the docking procedure are then tested in cell-based and cell-free assays (described below) to determine their efficacy in activating the insulin receptor.

[0043] Any compounds which show[ed] efficacy in the biological assays are then co- crystallized with IRK to verify binding in the JKI site, hi a further embodiment of the invention, candidate compounds capable of binding in the JKI site are modified by methods known in the art to further improve specific characteristics, e.g., to increase efficacy and/or specificity and/or solubility. Modifications that enhance cellular permeability, for example, may be particularly useful for therapeutic applications.

[0044] Selected compounds exhibiting the most desired characteristics are designated lead compounds, and further tested in, for example, diabetic mouse models to measure their efficacy.

Virtual Ligand Screening Via Flexible Docking Technology

[0045] Current docking and screening methodologies can select small sets of likely lead candidate ligands from large libraries of compounds using a specific receptor structure. Such methods are described, for example, in Abagyan and Totrov (2001) Current Opinion Chemical

Biology 5:375-382, herein specifically incorporated by reference in its entirety.

[0046] Virtual ligand screening (NLS) based on liigh-throughput flexible docking is useful for designing and identifying compounds able to bind to a specific receptor structure. NLS can be used to virtually sample a large number of chemical molecules without synthesizing and experimentally testing each one. Generally, the methods start with receptor modeling which uses a selected receptor structure derived by conventional means, e.g., X-ray crystallography, ΝMR, homology modeling. A set of compounds and/or molecular fragments are then docked into the selected binding site using any one of the existing docking programs, such as for example,

MCDOCK (Liu et al. (1999) J. Comput. Aided Mol. Des. 13:435-451), SEED (Majeux et al.

(1999) Proteins 37:88-105; DARWIN (Taylor et al. (2000) Proteins 41:173-191; MM (David et al. (2001) J. Comput. Aided Mol. Des. 15:157-171. Compounds are scored as ligands, and a list of candidate compounds predicted to possess the highest binding affinities are generated for further in vitro and in vivo testing and/or chemical modification.

[0047] In one approach of NLS, molecules are "built" into a selected binding pocket prior to chemical generation. A large number of programs are designed to "grow" ligands atom-by-atom [see, for example, G STAR (Pearlman et al. L(l 993) J. Comput. « in. 14: 1184), LEGEND (Nishibata et al. (1993) J. Med. Chem. 36:2921-2928), MCDNLG (Rotstein et al. (1993) J. Comput-Aided Mol. Des. 7:23-43), CONCEPTS (Gehlhaar et al. (1995) J. Med. Chem 38:466- 472] or fragment-by-fragment [see, for example, GROUPBUILD (Rotsein et al. (1993) J. Med. Chem. 36:1700-1710), SPROUT (Gillet et al. (1993) J. Comput. Aided Mol. Des. 7:127-153), LUDI (Bohm (1992) J. Comput. Aided Mol. Des. 6:61-78), BUILDER (Roe (1995) J. Comput. Aided Mol. Des. 9:269-282), and SMOG (DeWitte et al. (1996) J. Am. Chem. Soc. 118:11733- 11744].

[0048] Methods for scoring ligands for a particular receptor are known which allow discrimination between the small number of molecules able to bind the receptor structure and the large number of non-binders. See, for example, Agagyan et al. (2001) supra, for a report on the growing number of successful ligands identified via virtual ligand docking and screening methodologies.

[0049] For example, Nishibata et al. (1993) J. Med. Chem 36:2921-2928, describe the ability of a structure construction program to generate inhibitory molecules based on the three-dimensiona] structure of the active site of the dihydrofolate reductase molecule. The program was able to predict molecules having a similar structure to four known inhibitors of the enzyme, providing strong support that new lead compounds can be obtained with knowledge pertaining to the three dimensional structure of the target. Similarly, Gillet et al. (1993) J. Computer Aided Mol. Design 7:127-153 describe structure generation through artificial intelligence techniques based on steric constrains (SPROUT).

Agents Identified by the Screening Methods of the Invention

[0050] The invention provides methods for identifying agents (e.g., candidate compounds or test compounds) that bind with high affinity to the juxtamembrane-kinase interaction (JKI) site. Agents identified by the screening methods of the invention may be used as candidate anti- diabetic (type II) therapeutics.

[0051] Examples of agents, candidate compounds or test compounds include, but are not limited to, nucleic acids (e.g., DNA and RNA), carbohydrates, lipids, proteins, peptides, peptidomimetics, small molecules and other drugs. Agents may be obtained using any of the numerous approaches in combinatorial library methods known in the art, including: biological libraries; spatially addressable parallel solid phase or solution phase libraries; synthetic library methods requiring deconvolution; the "one-bead one-compound" library method; and synthetic library methods using affinity chromatography selection. The biological library approach is limited to peptide libraries, while the other four approaches are applicable to peptide, non- peptide oligomer or ( ill molecule libraries of compounds (Lam (H, ) Anticancer Drug Des.

IP irT T/' H ,. .,O 3 , fli p t qι p< 12:145; U.S. Patent JNo. 5,738,996; and U.S. Patent No. 5,807,683, each of which is^'mco pό atec herein in its entirety by reference).

[0052] Examples of methods for the synthesis of molecular libraries can be found in the art, for example in: DeWitt et al. (1993) Proc. Natl. Acad. Sci. USA 90:6909; Erb et al. (1994) Proc.

Natl. Acad. Sci. USA 91:11422; Zuckermann et al. (1994) J. Med. Chem. 37:2678; Cho et al.

(1993) Science 261:1303; Carrell et al. (1994) Angew. Chem. Int. Ed. Engl. 33:2059; Carell et al. (1994) Angew. Chem. Int. Ed. Engl. 33:2061; and Gallop et al. (1994) J. Med. Chem.

37:1233, each of which is incorporated herein in its entirety by reference.

[0053] Libraries of compounds may be presented, e.g., presented in solution (e.g., Houghten

(1992) Bio/Techniques 13:412-421), or on beads (Lam (1991) Nature 354:82- 84), chips (Fodor

(1993) Nature 364:555-556), bacteria (U.S. Patent No. 5,223,409), spores (Patent Nos. 5,571,698; 5,403,484; and 5,223,409), plasmids (Cull et al. (1992) Proc. Natl. Acad. Sci. USA 89:1865-1869) or phage (Scott and Smith (1990) Science 249:386-390; Devlin (1990) Science 249:404-406; Cwirla et al. (1990) Proc. Natl. Acad. Sci. USA 87:6378-6382; and Felici (1991) J. Mol. Biol. 222:301-310), each of which is incorporated herein in its entirety by reference.

Screening Assays

[0054] Small molecules identified through the above described virtual ligand docking and screening methodologies are further tested in in vitro and in vivo assays. In one embodiment, agents that interact with (i.e., bind to) the JKI site are identified in a cell-based assay system. In accordance with this embodiment, cells expressing an insulin receptor or a fragment thereof containing the JKI site, are contacted with a candidate compound or a control compound and the ability of the candidate compound to interact with the JKI is determined. If desired, this assay may be used to screen a plurality (e.g. a library) of candidate compounds. The cell, for example, can be of prokaryotic origin (e.g., E. coli) or eukaryotic origin (e.g., yeast or mammalian). Further, the cells can express the LR, or functional IR fragment, endogenously or be genetically engineered to express the LR, or functional IR fragment. In certain instances, the LR or functiona fragment thereof is labeled, for example with a radioactive label (such as ³²P, ³⁵S or ¹²⁵I) or a fluorescent label (such as fluorescein isothiocyanate, rhodamine, phycoerythrin, phycocyanin, allophycocyanin, o-phthaldehyde or fluorescamine) to enable detection of an interaction between the IR and a candidate compound. The ability of the candidate compound to bind to the JKI site can be determined by methods known to those of skill in the art. For example, the interaction between a candidate compound and the JKI site can be determined by flow cytometry, a scintillation assay, immunoprecipitation or western blot analysis. [0055] In another eri diment, agents that interact with (i.e., bind t he JKI site of the LR, or a functional fragment thereof, are identified m a cell-free a pssacyT sys/te^'mu,^ja hTi acco/rdaunⁱcKe- w.iit'hΩ tehis embodiment, a native or recombinant IR or fragment thereof is contacted with a candidate compound or a control compound and the ability of the candidate compound to interact with the JKI site of the LR is determined. If desired, this assay may be used to screen a plurality (e.g. a library) of candidate compounds. In one embodiment, the IR or fragment thereof is first immobilized by contacting it with, for example, an immobilized antibody which specifically recognizes and binds it, or by contacting a purified preparation of the IR or fragment thereof, with a surface designed to bind proteins. The IR or JKI site-containing LR fragment may be partially or completely purified (e.g., partially or completely free of other polypeptides) or part of a cell lysate. Further, the IR or JKI site-containing IR fragment may be a fusion protein comprising the JKI site or a biologically active portion thereof, and a domain such as glutathionine-S-transferase. Alternatively, the IR or JKI-containing fragment thereof can be biotinylated using techniques well known to those of skill in the art (e.g., biotinylation kit, Pierce Chemicals; Rockford, IL). The ability of the candidate compound to interact with the JKI site can be determined by methods known to those of skill in the art.

[0056] In another embodiment, agents that modulate the constitutive inhibition of LR kinase activity are identified in an animal model. Agents that abrogate the constitutive inhibition of IR kinase activity (i.e., activators of IR kinase activity), for example, may be identified in animal models. Examples of suitable animals include, but are not limited to, mice, rats, rabbits, monkeys, guinea pigs, dogs and cats. Preferably, the animal used provides an animal model system for type II diabetes. In accordance with this embodiment, the test compound or a control compound is administered (e.g., orally, rectally or parenterally such as intraperitoneally or intravenously) to a suitable animal and the effect on the level of LR kinase activity is determined.

Antibodies to the JKI Site

[0057] The invention provides a site on the three-dimensional surface of LRK, termed the juxtamembrane-kinase interaction (JKI) site, responsible in part for suppressing the activity of the insulin receptor. Accordingly, the JKI site and antigenic fragments thereof are useful for generating antibodies immunospecific for the JKI site. As used herein, an antigenic fragment of the JKI site refers to a part or portion of the JKI site that elicits an immunological response when used as an antigen. Such immunological responses generally result in the generation of antibodies immunologically specific for the JKI site. Antibodies which are immunologically specific for the JKI site are capable of recognizing the JKI site largely to the exclusion of other si! Anti-J i antibodies may be produced by id ods and techniques known to one of skill in the art. The anti- JKI antibodies of the invention may be used in a variety of applications. Such applications include their use as potential therapeutics capable of blocking the binding of an endogenous ligand to the JKI site, and thus "de-repressing" or activating the tyrosine kinase domain of the insulin receptor.

Exemplary Methods of Use for the JKI Site Binding Agents.

[0058] The invention provides for the treatment and/or prevention of type II diabetes by administration of a therapeutic agent/compound identified using the above described methods.

Such compounds include but are not limited to proteins, peptides, protein or peptide derivatives or analogs, antibodies, nucleic acids, and small molecules.

[0059] The invention provides methods of treatment (and/or prophylaxis) of type II diabetes comprising administering to a subject an effective amount of a compound identified by a method of the invention. In a preferred aspect, the compound is substantially purified (e.g., substantially free from substances that limit its effect or produce undesired side-effects). The subject is preferably an animal, including but not limited to animals such as cows, pigs, horses, chickens, cats, dogs, etc., and is preferably a mammal, and most preferably human. In a specific embodiment, a non-human mammal is the subject.

[0060] Formulations and methods of administration that can be employed when the compound comprises a nucleic acid are described above; additional appropriate formulations and routes of administration are described below.

[0061] Various delivery systems are known and can be used to administer a compound of the invention, e.g., encapsulation in liposomes, microparticles, microcapsules, recombinant cells capable of expressing the compound, receptor-mediated endocytosis (see, e.g., Wu and Wu

(1987) J. Biol. Chem. 262:4429-4432), construction of a nucleic acid as part of a retroviral or other vector, etc. Methods of introduction can be enteral or parenteral and include but are not limited to intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes. The compounds may be administered by any convenient route, for example by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.) and may be administered together with other biologically active agents. Administration can be systemic or local. In addition, it may be desirable for some applications to introduce the pharmaceutical compositions of the invention into the central nervous system (CNS) by any suitable route, including intraventricular and intrathecal injection; intraventricular injection may be facilitated by an intraventricular catheter, for example, attached to a reservoir, such as an Ommaya reservoir. Pulmonary administration can z >e employed, e.g., by use of an inhaler or ne izer, and formulation with

I C T s' U ϊa II I:;:! .^■■■" O .1. *iϊ iEU an aerosolizing agent.

[0062] In a specific embodiment, the compound can be delivered in a vesicle, in particular a liposome (see Langer (1990) Science 249:1527-1533; Treat et al., in Liposomes in the Therapy of Infectious Disease and Cancer, Lopez-Berestein and Fidler (eds.), Liss, New York, pp. 353-

365 (1989); Lopez-Berestein, ibid., pp. 317-327; see generally ibid.)

[0063] In a specific embodiment, it may be desirable to administer the pharmaceutical compositions of the invention locally, e.g., by local infusion during surgery, topical application, e.g., by injection, by means of a catheter, or by means of an implant, said implant being of a porous, non-porous, or gelatinous material, including membranes, such as sialastic membranes, or fibers.

[0064] In yet another embodiment, the compound can be delivered in a controlled release system, hi one embodiment, a pump may be used (see Langer, supra; Sefton (1987) CRC Crit.

Ref. Biomed. Eng. 14:201; Buchwald et al. (1980) Surgery 88:507; Saudek et al., 1989, N. Engl.

J. Med. 321:574). In another embodiment, polymeric materials can be used (see Medical

Applications of Controlled Release, Langer and Wise (eds.), CRC Pres., Boca Raton, Florida

(1974); Controlled Drug Bioavailability, Drug Product Design and Performance, Smolen and

Ball (eds.), Wiley, New York (1984); Ranger and Peppas, J., 1983, Macromol. Sci. Rev.

Macromol. Chem. 23:61; see also Levy et al. (1985) Science 228:190; During et al. (1989) Ann.

Neurol. 25:351; Howard et al. (1989) J. Neurosurg. 71:105). In yet another embodiment, a controlled release system can be placed in proximity of the therapeutic target, e.g., the pancreas, thus requiring only a fraction of the systemic dose (see, e.g., Goodson, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138 (1984)).

[0065] Other controlled release systems are discussed in the review by Langer (1990, Science

249:1527-1533).

Pharmaceutical Compositions

[0066] The present invention also provides pharmaceutical compositions. Such compositions comprise a therapeutically effective amount of an agent, and a pharmaceutically acceptable carrier. In a particular embodiment, the term "pharmaceutically acceptable" means approved by a regulatory agency of the Federal or a state government or listed in the

U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans. The term "carrier" refers to a diluent, adjuvant, excipient, or vehicle with which the therapeutic is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peani 1, soybean oil, mineral oil, sesame oil and tL ke. Water is a

P C T. ι α3/^μ O iι _røe preferred carrier when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. The composition, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. These compositions can take the form of solutions, suspensions, emulsion, tablets, pills, capsules, powders, sustained-release formulations and the like. The composition can be formulated as a suppository, with traditional binders and carriers such as triglycerides. Oral formulation can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc. Examples of suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by E.W.

Martin, which is incorporated herein in its entirety by reference. Such compositions will contain a therapeutically effective amount of the compound, preferably in purified form, together with a suitable amount of carrier so as to provide a form for proper administration to a subject. The formulation should suit the mode of administration.

[0067] In a preferred embodiment, the composition is formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous administration to human beings. Typically, compositions for intravenous administration are solutions in sterile isotonic aqueous buffer. Where necessary, the composition may also include a solubilizing agent and a local anesthetic such as lidocaine to ease pain at the site of the injection.

Generally, the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampoule or sachette indicating the quantity of active agent.

Where the composition is to be administered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline. Where the composition is administered by injection, an ampoule of sterile water for injection or saline can be provided so that the ingredients may be mixed prior to administration.

[0068] The compounds of the invention can be formulated as neutral or salt forms.

Pharmaceutically acceptable salts include those formed with free amino groups such as those derived from hydrochloric, phosphoric, acetic, oxalic, tartaric acids, etc., and those formed with free carboxyl groups such as those derived from sodium, potassium, ammonium, calcium, ferric hydrr, _ΞS, isopropylamine, triethylamine, 2-etnylar ) ethanol, histidine,

procaine, etc.

[0069] The amount of a compound identified using the methods of the invention which provides a therapeuticaly effective dose in the treatment of a patient with type II diabetes and related disorders can be determined by standard clinical techniques based on the present description. In addition, in vitro assays may optionally be employed to help identify optimal dosage ranges. The precise dose to be employed in the formulation will also depend on the route of administration, and the seriousness of the disease or disorder, and should be decided according to the judgment of the practitioner and each subject's circumstances. However, suitable dosage ranges for intravenous administration are generally about 20-500 micrograms of active compound per kilogram body weight. Suitable dosage ranges for intranasal administration are generally about 0.01 pg/kg body weight to 1 mg/kg body weight. Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems.

[0070] Suppositories generally contain active ingredient in the range of 0.5% to 10% by weight; oral formulations preferably contain 10%) to 95% active ingredient.

Nucleic Acids

[0071] The invention provides methods of identifying agents capable of binding the JKI site to activate (or decrease constitutive inhibition) of the tyrosine kinase activity of the insulin receptor.

Accordingly, the invention encompasses administration of a nucleic acid encoding a peptide or protein activator of the tyrosine kinase domain, as well as antisense sequences or catalytic RNAs capable of interfering with the expression of a natural inhibitor of the tyrosine kinase activity of an insulin receptor.

[0072] In one embodiment, a nucleic acid comprising a sequence encoding a peptide or protein capable of competitively binding to the JKI site of the insulin receptor is administered. Any suitable methods for administering a nucleic acid sequence available in the art can be used according to the present invention.

[0073] Methods for administering and expressing a nucleic acid sequence are generally known in the area of gene therapy. For general reviews of the methods of gene therapy, see

Goldspiel et al. (1993) Clinical Pharmacy 12:488-505; Wu and Wu (1991) Biotherapy

3:87-95; Tolstoshev (1993) Ann. Rev. Pharmacol. Toxicol. 32:573-596; Mulligan (1993)

Science 260:926-932; and Morgan and Anderson (1993) Ann. Rev. Biochem. 62:191-217;

May (1993) TLBTECH 11(5): 155-215. Methods commonly known in the art of recombinant

DNA technology which can be used in the present invention are described in Ausubel et al. (eds.), 1993, Curren Dtocols in Molecular Biology, John Wjley as. NY;, and Kriegler

P L. II . Lv :::::i' U .-^■ O id! L 'Qι id!

(1990) Gene Transfer and Expression, A Laboratory Manual, Stockton Press, NY.

[0074] In a particular aspect, the compound comprises a nucleic acid encoding a peptide or protein capable of competitively binding to the JKI site of the insulin receptor and diminishing constitutive or intrinsic inhibition of tyrosine kinase activity, such nucleic acid being part of an expression vector that expresses the peptide or protein in a suitable host. In particular, such an expression vector has a promoter and/or enhancer operably linked to the coding region, said promoter being inducible or constitutive (and, optionally, tissue-specific).

In another particular embodiment, a nucleic acid molecule is used in which the coding sequences and any other desired sequences are flanked by regions that promote homologous recombination at a desired site in the genome, thus providing for intrachromosomal expression of the nucleic acid (Koller and Smithies (1989) Proc. Natl. Acad. Sci. USA

86:8932-8935; Zijlstra et al. (1989) Nature 342:435-438).

[0075] Delivery of the nucleic acid into a subject may be direct, in which case the subject is directly exposed to the nucleic acid or nucleic acid-carrying vector; this approach is known as in vivo gene therapy. Alternatively, delivery of the nucleic acid into the subject may be indirect, in which case cells are first transformed with the nucleic acid in vitro and then transplanted into the subject, known as "ex vivo gene therapy".

[0076] In another embodiment, the nucleic acid is directly administered in vivo, where it is expressed to produce the encoded product. This can be accomplished by any of numerous methods known in the art, e.g., by constructing it as part of an appropriate nucleic acid expression vector and administering it so that it becomes intracellular, e.g., by infection using a defective or attenuated retroviral or other viral vector (see U.S. Patent No. 4,980,286); by direct injection of naked DNA; by use of microparticle bombardment (e.g., a gene gun;

Biolistic, Dupont); by coating with lipids, cell-surface receptors or transfecting agents; by encapsulation in liposomes, microparticles or microcapsules; by administering it in linkage to a peptide which is known to enter the nucleus; or by administering it in linkage to a ligand subject to receptor-mediated endocytosis (see, e.g., Wu and Wu, 1987, J. Biol. Chem.

262:4429-4432), winch can be used to target cell types specifically expressing the receptors.

In another embodiment, a nucleic acid-ligand complex can be formed in which the ligand comprises a fusogenic viral peptide to disrupt endosomes, allowing the nucleic acid to avoid lysosomal degradation. In yet another embodiment, the nucleic acid can be targeted in vivo for cell specific uptake and expression, by targeting a specific receptor (see, e.g., PCT

Publications WO 92/06180 dated April 16, 1992 (Wu et al.); WO 92/22635 dated December

23, 1992 (Wilson et al.); WO92/20316 dated November 26, 1992 (Findeis et al.);

(Young)). Alternatively, the nucleic acid can be introduced intracellularly and incorporated within host cell DNA for expression, by homologous recombination (Koller and Smithies,

1989, Proc. Natl. Acad. Sci. USA 86:8932-8935; Zijlstra et al. (1989) Nature 342:435-438).

[0077] In a further embodiment, a retroviral vector can be used (see Miller et al. (1993)

Meth. Enzymol. 217:581-599). These retroviral vectors have been modified to delete retroviral sequences that are not necessary for packaging of the viral genome and integration into host cell DNA. The nucleic acid encoding the protein to be used in gene therapy is cloned into the vector, which facilitates delivery of the gene into a subject. More detail about retroviral vectors can be found in Boesen et al. (1994) Biotherapy 6:291-302, which describes the use of a retroviral vector to deliver the mdrl gene to hematopoietic stem cells in order to make the stem cells more resistant to chemotherapy. Other references illustrating the use of retroviral vectors in gene therapy are: Clowes et al. (1994) J. Clin. Invest. 93:644-651; Kiem et al. (1994) Blood 83:1467-1473; Salmons and Gunzberg (1993) Human Gene Therapy

4:129-141; and Grossman and Wilson (1993) Curr. Opin. in Genetics and Devel. 3:110-114.

[0078] Other viral vectors, including adenoviruses, may be used in gene therapy.

Adenoviruses are especially attractive vehicles for delivering genes to respiratory epithelia.

Adenoviruses naturally infect respiratory epithelia, the infection of which results in a mild respiratory disease. Other targets for adenovirus-based delivery systems are the liver, the central nervous system, endothelial cells, and muscle. Adenoviruses have the advantage of being capable of infecting non-dividing cells. Kozarsky and Wilson (1993) Current Opinion in Genetics and Development 3:499-503 present a review of adenovirus-based gene therapy.

Bout et al. (1994) Human Gene Therapy 5:3-10 demonstrated the utility of adenovirus vectors for introducing genes into the respiratory epithelia of rhesus monkeys. Other instances pertaining to the use of adenoviruses in gene therapy can be found in Rosenfeld et al. (1991) Science 252:431-434; Rosenfeld et al. (1992) Cell 68:143-155; Mastrangeli et al.

(1993) J. Clin. Invest. 91:225-234; PCT Publication WO94/12649; and Wang, et al. (1995)

Gene Therapy 2:775-783. Adeno-associated virus (AAV) has also been proposed for use in gene therapy (Walsh et al. (1993) Proc. Soc. Exp. Biol. Med. 204:289-300; U.S. Patent No.

5,436,146).

[0079] Another suitable approach to gene therapy involves transferring a gene to cells in tissue culture by methods such as, for example, viral infection and electroporation-mediated, liposome-mediated, or calcium phosphate-mediated transfection. Usually, the method of transfer also includes the transfer of a selectable marker into the cells. The cells are then placed under selectio o isolate those cells that have been products transfected, Such

I! πC ^"II^" , ■^••• ,3 (13 .."' ^' ϋ ii!::!! ,1. Q S selected cells are then delivered to a subject.

[0080] In this embodiment, the nucleic acid is introduced into a cell prior to administration of the resulting recombinant cell in vivo. Such introduction can be carried out by any method known in the art, including, but not limited to, transfection, microinjection, infection with a viral or bacteriophage vectors comprising the desired nucleic acid sequences, cell fusion, chromosome-mediated gene transfer, microcell-mediated gene transfer, and spheroplast fusion. Numerous techniques are known in the art for the introduction of foreign genes into cells (see, e.g., Loeffler and Behr (1993) Meth. Enzymol. 217:599-618; Cohen et al. (1993) Meth. Enzymol. 217:618-644; Cline (1985) Pharmac. Ther. 29:69-92) and may be used in accordance with the present invention, provided that the necessary developmental and physiological functions of the recipient cells are not disrupted. Such a technique provides for the stable transfer of the nucleic acid to the cell, so that the nucleic acid is expressible by the cell and preferably heritable and expressible by its cell progeny.

[0081] The resulting recombinant cells can be delivered to a subject by various methods known in the art. In a preferred embodiment, epithelial cells are injected, e.g., subcutaneously. In another embodiment, recombinant skin cells may be applied as a skin graft onto the subject; recombinant blood cells (e.g., hematopoietic stem or progenitor cells) are preferably administered intravenously. The amount of cells envisioned for use depends on the desired effect, the condition of the subject, etc., and can be determined by one skilled in the art.

[0082] Cells into which a nucleic acid can be introduced for purposes of gene therapy encompass any desired, available cell type, and include but are not limited to hepatocyte cells, muscle cells, glial cells (e.g., oligodendrocytes or astrocytes), epithelial cells, endothelial cells, keratinocytes, and fibroblasts; blood cells such as T lymphocytes, B lymphocytes, monocytes, macrophages, neutrophils, eosinophils, megakaryocytes, granulocytes; and various stem or progenitor cells, in particular hematopoietic stem or progenitor cells, e.g., as obtained from bone marrow, umbilical cord blood, peripheral blood or fetal liver. In a preferred embodiment, the cell used for gene therapy is autologous to the subject that is treated.

[0083] In an embodiment in which recombinant cells are used in gene therapy, a nucleic acid encoding an agent (e.g., a peptide or protein) capable of increasing the activity of an insulin receptor is introduced into cells such that it is expressible by the cells and/or their progeny, and the recombinant cells are then administered in vivo for therapeutic effect. In a specific embodiment, stem or progenitor cells are used. Any stem or progenitor cells which can be isolated and maintaii present invention (see

Anderson (1992) Cell 71:973-985; Rheinwald (1980) Meth. Cell Bio. 21A:229; and Pittelkow and Scott (1986) Mayo Clinic Proc. 61:771).

[0084] In another embodiment, the nucleic acid to be introduced for purposes of gene therapy may comprise an inducible promoter operably linked to the coding region, such that expression of the nucleic acid is controllable by regulating the presence or absence of the appropriate inducer of transcription.

[0085] Direct injection of a DNA coding for a peptide or protein capable of binding to the JKI site of the insulin receptor or an agent capable of interfering with the expression of an endogenous inhibitor of the tyrosine kinase activity of the insulin receptor may also be performed according to, for example, the techniques described in United States Patent No. 5,589,466. These techniques involve the injection of "naked DNA", i.e., isolated DNA molecules in the absence of liposomes, cells, or any other material besides a suitable carrier. The injection of DNA encoding a protein and operably linked to a suitable promoter results in the production of the protein in cells near the site of injection and the elicitation of an immune response in the subject to the protein encoded by the injected DNA.

Kits

[0086] The invention also provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention. Optionally associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects (a) approval by the agency of manufacture, use or sale for human administration, (b) directions for use, or both.

EXAMPLES

[0087] The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the assay, screening, and therapeutic methods of the invention, and are not intended to limit the scope of the invention. Unless indicated otherwise, parts are parts by weight, molecular weight is average molecular weight, temperature is in degrees Centigrade, and pressure is at or near atmospheric.

Example 1. Importance of Y984 in Maintaining Basal-State Kinase Activity

[0088] A mutant form of IRK was expressed and purified in which Y984 was replaced by phenylalanine (Y984 The crystal structure of the Y984F mutant, ys,,that the JM regicmis

!l ' I... ii .^•■' IL 'l:::n LI 3..^■■ II. J tι:_L.l"^r.i» id! in a different conformation than in wild-type IRK, i.e, the JKI site is less effectively masked. In vitro kinase assays of the soluble tyrosine kinase domain indicate that the activity of the Y984F mutant kinase was approximately three-fold higher than that of the wild-type kinase in the pre- activated, unphosphorylated state (Table I). The data suggest that an assay based on JKI site binding could be used to advantage to identify compounds capable of binding with high affinity to the JKI site as it exists in the activated state of the kinase (Figs. 3-4). Compounds able to bind to the JKI site with high affinity would compete with Y984 for the JKI site, displacing the JM region, and facilitating the pivoting of α-helix C, resulting in stimulation of basal (constitutive) kinase activity.

[0089] Modifications were introduced into the JM region of the IR. The basal-state and insulin- stimulated autophosphorylated levels of the mutant receptor were examined in transiently transfected HEK 293T cells.

[0090] Site directed mutagenesis. A point mutation of Y984 was introduced to examine the role of this LR subfamily-invariant residue in the insulin-induced structural transition. Site-directed mutagenesis was performed with the QuickChange system (Stratagene), a fast, PCR-based protocol. The insert region of all PCR-generated expression vectors was sequenced to assure that no extraneous mutations were introduced during the PCR process.

[0091] Baculovirus/insect cell expression of IRK proteins. A baculovirus/insect cell expression system was used to produce IR cytoplasmic proteins. Generation of new recombinant baculovirus constructs was done with the Bac-to-Bac system (Gibco BRL). For protein production, 15 cm dishes were seeded with 1.5xl0⁷ Sf9 cells each and recombinant baculovirus was added at a multiplicity of infection (MOI) of ~10. After 48-72 hours, cells were harvested and centrifuged, and the cell pellets were either lysed directly or flash-frozen and stored at - 80°C.

[0092] Purification of the phosphorylated forms of IRK. IRK-OP was purified from baculovirus-infected Sf9 cell lysates in three FPLC chromatography steps: Source Q anion- exchange chromatography, Superdex 75 gel filtration chromatography, and Mono Q anion- exchange chromatography. The typical yield was ~2 mg of purified protein from 1 L of cultured Sf9 cells with a purity >95%. To produce IRK-2P and IRK-3P, a small-scale autophosphorylation experiment was carried out on purified IRK-OP by adding 20 mM ATP and 50 mM MgCl (final concentrations). Large-scale autophosphorylation was then performed and terminated by the addition of EDTA (50-100 mM final). The autophosphorylated forms of LRK were purified by Mono Q or Source Q chromatography.

[0093] Transient transfection of mutant LRs in HEK 293T cells. HEK 293T cells were plated

9? one day prior to trari tion in DMEM + 10% FBS without antibiol After 24 hr, the

P i:;: T . -' us o .- ^■ ιι.:J K w i_* monolayer of cells was incubated with 10 μg of pEF-LR DNA and 60 μl LipofectAMLNE 2000 (Gibco-BRL) for 5 hr. The media was removed and replaced with DMEM + 10% FBS with antibiotics. Transiently transfected 293T cells were split and plated 24 hr post-transfection. At 48 hr post-transfection, cells were starved with serum-free DMEM for 3 hours, stimulated with insulin for 5 min at 37°C, and immediately chilled and washed with ice-cold PBS. The cell lysates were subjected to 10%o SDS-PAGE, and protein bands were transferred onto nitrocellulose membranes. Membranes were blotted with anti-phosphotyrosine antibody and visualized using enhanced chemiluminescence. The membrane was subsequently stripped, washed, and blotted with anti-IRK antibody.

[0094] Steady-state kinetics. Two types of kinase assays were employed, the coupled assay and the phosphocellulose-paper assay. In the coupled assay, kinase activity is measured by a continuous spectrophotometric assay in which the production of ADP is coupled to the oxidation of NADH and monitored as a reduction in absorbance at 340 nm. In the phosphocellulose-paper assay, reactions are typically carried out at 30°C in a reaction buffer containing 100-500 cpm/pmol [γ- P]-ATP. Fixed or varied peptide substrate and fixed or varied ATP was included in the mixture, depending on the experiment. Reactions were terminated by the addition of 30%> ice-cold trichloroacetic acid and spotted onto p81 phosphocellulose paper. The phosphocellulose filters were washed in phosphoric acid, dried, and counted in a scintillation counter to measure incoφoration of ³²P into the peptide substrate. Initial rate conditions were determined by plotting enzyme activity as a function of time. Linear portions of this curve were used to calculate the enzyme velocity for each condition under examination. A velocity vs. substrate (peptide, ATP or Mg²⁴) plot was fit to the Michaelis-Menten equation using nonlinear regression analysis software (GraFit).

[0095] Crystallization and data collection. The conventional method of vapor diffusion in hanging and sitting drops may be used for crystallization trials. Alternative crystallization techniques such as microdialysis may also be employed. X-ray diffraction data may be measured, for example, on an R-AXIS IIC image plate system atop a Rigaku RU-200 rotating anode source equipped with crystal cryo-cooling (Oxford Cryosystems). For high-resolution data collection, synchrotron x-ray sources may be used.

Example 2. In Vitro Determination of Binding to JKI

[0096] Cell-free assay: The test compound at various concentrations is incubated with purified

IRK (residues 978-1283) for 10 minutes, ATP is added, and the rate of autophosphorylation is measured by taking I uots of the reaction at various time points an unning the aliquots on a C T/ u S O J / O Ξ l '-i r* native (non-denaturing) PAGE gel as described by Wei et al. (1995) J. Biol. Chem. 270, 8122-

8130. In a second cell-free assay, the test compound is incubated at various concentrations with purified LRK, ATP and substrate peptide added, and the rate of phosphate incoφoration into the substrate peptide is monitored by a coupled assay spectrophotometric method as described by

Barker et al. (1995) Biochemistry 34, 14843-14851, or by using radioactive phosphate (³²P) and measuring phosphate incoφoration with a scintillation counter.

[0097] Cell-based assay: Chinese hamster ovary cells stably transfected with the wild-type insulin receptor (CHO-IR) are starved with serum-free DMEM for 3 hr and then incubated with the test compound for 10 minutes. The cells are then stimulated for 5 minutes with various concentrations of insulin (0-100 nM). Cell lysates and/or immunoprecipitates are subjected to

SDS-PAGE, and the nitrocellulose transfer membranes are immunoblotted with anti- phosphotyrosine antibody to assay phosphotyrosme levels, and subsequently stripped and blotted with anti-IR antibody to show that equal numbers of receptors are expressed.

[0098] Determination of Activation of Insulin Receptor. To determine whether a test compound capable of activating the insulin receptor does so by binding to the JKI site, the compound is incubated with phosphorylated IRK and crystals are obtained of the compound-IRK complex.

X-ray diffraction data are collected and the difference in the electron density between IRK alone and the compound bound to IRK reveals whether the compound binds in the JKI site.

Example 3: Screening Small Molecules with the JKI Site

[0099] The three-dimensional structure of IRK at the JKI site (APPENDIX A) is used as a target in a virtual ligand screening procedure to identify, via computer docking methods, compounds from a vast compound library which are capable of binding with high affinity to the target site. Specifically, the trial compounds are docked to the JKI site and binding energetics predicted. Compounds from the virtual ligand screen scoring the highest in the docking procedure are tested in cell-based and cell-free assays to determine their efficacy for activation of the insulin receptor. Compounds with the best binding and solubility properties are then tested in diabetic mouse models to measure their efficacy in vivo.

Example 4: Effect of JKI Mutations on Insulin Receptor Activity

[0100] Two mutant IR molecules, designated Y984F and Y984A, were generated as described above. The introduction of either one of these mutations into an IR molecule produces an LR molecule in which the JKI site is unoccupied. The activity of the two mutant molecules was measured as described above. Table I shows that the mutant LRK Y984F (unphosphorylated) was more active ma_* Id-type IRK (unphosphorylated) in vitro. T _^ 11 shows that the

IP C T/ S Q 3 , ' U H ,;l. ^,!'l a phosphorylation level of the mutant Y984A insulin receptor (full-length) in 293T mammalian cells was highly elevated as compared to that of wild-type insulin receptors. Of note, the elevated phosphorylation level of the Y984A mutant was observed in the presence or absence of insulin stimulation.

Table I. Determination of Insulin Receptor Kinase Activity in vitro

Table II. Phosphorylation Level of Y984A Insulin Receptor Versus Wild-type Insulin Receptor ₁ in 293T Cells

Example 5: Evaluating Effect of JKI Binding Agents on Activity of Tyrosine Kinases with Sites Analogous to the JKI Site of the Insulin Receptor

[0101] Since the JKI site is common to all RTK family members, an agent identified using the methods of the invention may be tested for the ability to bind and modulate the activity of other RTK family members. For example, Tyr-822 in the juxtamembrane region of the vascular endothelial growth factor receptor-2 (NEGFR2) occupies a similar position in the JKI site of NEGFR2 as that of Tyr-984 in the JKI site of the insulin receptor. Similarly, Leu- 465 in the fibroblast growth factor receptor- 1 (FGFR1) is bound in the JKI site of FGFR1. Small molecule displacement of Tyr-822 or Leu-465 from the JKI site of NEGFR2 or FGFR1, respectively, could result in partial activation of these RTKs. Small molecules or agents that are capable of modulating the activity of NEGFR2 or FGFR1 may be used to advantage in the treatment of patients with disorders characterized by aberrant activity of these RTKS. Disorders that may be treated by NEGF receptor inliibitors include, but are not limited to, cancers in which it is desirable to inhibit tumor angiogenesis. Disorders which may be treated by NEGF receptor activators include, but are not limited to, disorders/conditions in which it is desirable to promote vascularization. NEGF receptor activators may be used, for example, to promote wound healing and/or vascularization of transplanted organs and/or grafts to enhance their viability. Disorders that may be treated by FGFR receptor inhil s include, but are not limited to, cancers in ^Λ .ch it is desirable to C T/^, O S U 3 /^,, O e A ^,y i£! inhibit tumor angiogenesis and craniofacial disorders, such as Crouzon Syndrome and Apert

Syndrome. FGFR receptor activators may be used to advantage to promote wound healing and/or vascularization.

[0102] The methods of the present invention may also be useful with regard to their application to the JKI sites of other RTKs (i.e., RTKs other than the insulin receptor).

Specifically, the methods of the present invention may be applied to identifying agents capable of binding to the JKI sites of other RTKs. Those agents identified by such means may be tested for their ability to modulate the activity of the particular RTK from which the

JKI was derived. An agent capable of modulating the activity of a particular RTK may be further tested to evaluate if the agent is also capable of modulating the activity of other

RTKS, including the insulin receptor. In accordance with the present invention, an agent so identified that is capable of selectively activating the insulin receptor may be used to advantage to treat a patient with type II diabetes.

HEADER COMPLEX (TRANSFERASE/SUBSTRATE) 22-SEP-97 1IR3

TITLE PHOSPHORYLATED INSULIN RECEPTOR TYROSINE KINASE IN COMPLEX

TITLE 2 WITH PEPTIDE SUBSTRATE AND ATP ANALOG

COMPND MOL_ID : 1 ;

COMPND MOLECULE : INSULIN RECEPTOR;

COMPND CHAIN: A;

COMPND FRAGMEN : TYROSINE KINASE DOMAIN;

COMPND EC: 2.7.1..112;

COMPND ENGINEERED: YES;

COMPND 7 MUTATION: C981S, Y984F;

COMPND 8 BIOLOGICAL_UNIT: TETRAMER OF 2 ALPHA AND 2 BETA CHAINS

COMPND 9 LINKED BY DISULFIDE BONDS;

COMPND 10 MOL_ID: 2 ;

COMPND 11 MOLECULE: PEPTIDE SUBSTRATE;

COMPND 12 CHAIN: B;

COMPND 13 ENGINEERED: YES

SOURCE MOL__ID : 1 ;

SOURCE 2 ORGANISM_SCIENTIFIC : HOMO SAPIENS;

SOURCE 3 ORGANISM_COMMON: HUMAN;

SOURCE 4 ΞXPRESSION_SYSTEM: SPODOPTERA FRUGIPERDA INSECT CELLS;

SOURCE 5 EXPRΞSSION_SYSTΞM_STRAIN: SF9 ;

SOURCE 6 EXPRESSION_SYSTEM_CΞLLULAR_LOCATION: CYTOPLASM;

SOURCE 7 EXPRESSION_SYSTEM_VECTOR_TYPE: BACULOVIRUS;

SOURCE 8 MOL_ID: 2;

SOURCE 9 SYNTHETIC: DERIVED FROM PHOSPHORYLATION SITE TYR 727 ON RAT

SOURCE 10 IRS-1

KEY DS TYROSINE KINASE, SIGNAL TRANSDUCTION, PHOSPHOTRANSFERASE,

KEY DS 2 COMPLEX (KINASE/PEPTIDE SUBSTRATE/ATP ANALOG) , ENZYME,

KEYWDS 3 COMPLEX (TRANSFERASE/SUBSTRATE)

EXPDTA X-RAY DIFFRACTION

AUTHOR S . R.HUBBARD

REVDAT 1 07-JAN-98 1IR3 0

JRNL AUTH S .R .HUBBARD

JRNL TITL CRYSTAL STRUCTURE OF THE ACTIVATED INSULIN RECEPTOR

JRNL TITL 2 TYROSINE KINASE IN COMPLEX WITH PEPTIDE SUBSTRATE

JRNL TITL 3 AND ATP ANALOG

JRNL REF EMBO J. V. 16 5572 1997

JRNL REFN ASTM EMJODG UK ISSN 0261-4189 0897

REMARK

REMARK REFERENCE 1

REMARK AUTH S .R .HUBBARD, L .WEI , L . ELLIS ,W.A. HENDRICKSON

REMARK TITL CRYSTAL STRUCTURE OF THE TYROSINE KINASE DOMAIN OF

REMARK TITL 2 THE HUMAN INSULIN RECEPTOR

REMARK REF NATURE V. 372 746 1994

REMARK REFN ASTM NATUAS UK ISSN 0028-0836 0006

REMARK

REMARK RESOLUTION. 1.9 ANGSTROMS .

REMARK

REMARK REFINEMENT .

REMARK PROGRAM X-PLOR 3. 816

REMARK AUTHORS BRUNGER

REMARK

REMARK DATA USED IN REFINEMENT.

REMARK RESOLUTION RANGE HIGH (ANGSTROMS)

REMARK RESOLUTION RANGE LOW (ANGSTROMS)

REMARK DATA CUTOFF (SIGMA (F) )

REMARK DATA CUTOFF HIGH (ABS (F) ) 100000. REMARK 3 DATA CUTOFF LOW (ABS(F)) 0.1 REMARK 3 COMPLETENESS (WORKING+TEST) (%) 90.2 REMARK 3 NUMBER OF REFLECTIONS 25082 REMARK 3 REMARK 3 FIT TO DATA USED IN REFINEMENT. REMARK 3 CROSS-VALIDATION METHOD THROUGHOUT REMARK 3 FREE R VALUE TEST SET SELECTION RANDOM REMARK 3 R VALUE (WORKING SET) 0.194 REMARK 3 FREE R VALUE 0.226 REMARK 3 FREE R VALUE TEST SET SIZE (%) 4.5 REMARK 3 FREE R VALUE TEST SET COUNT 1261 REMARK 3 ESTIMATED ERROR OF FREE R VALUE 0.006 REMARK 3 REMARK 3 FIT IN THE HIGHEST RESOLUTION BIN. REMARK 3 TOTAL NUMBER OF BINS USED 10 REMARK 3 BIN RESOLUTION RANGE HIGH (A) 1.90 REMARK 3 BIN RESOLUTION RANGE LOW (A) 1.97 REMARK 3 BIN COMPLETENESS (WORKING+TEST) (%) 70.2 REMARK 3 REFLECTIONS IN BIN (WORKING SET) 1812 REMARK 3 BIN R VALUE (WORKING SET) 0.189 REMARK 3 BIN FREE R VALUE 0.223 REMARK 3 BIN FREE R VALUE TEST SET SIZE (%) 3.7 REMARK 3 BIN FREE R VALUE TEST SET COUNT 102 REMARK 3 ESTIMATED ERROR OF BIN FREE R VALUE 0.020 REMARK 3 REMARK 3 NUMBER OF NON-HYDROGEN ATOMS USED IN REFINEMENT. REMARK 3 PROTEIN ATOMS 2406 REMARK 3 NUCLEIC ACID ATOMS NULL REMARK 3 HETEROGEN ATOMS 45 REMARK 3 SOLVENT ATOMS 202 REMARK 3 REMARK 3 B VALUES. REMARK 3 FROM WILSON PLOT (A**2) NULL REMARK 3 MEAN B VALUE (OVERALL, A**2) 18.9 REMARK 3 OVERALL ANISOTROPIC B VALUE. REMARK 3 Bll (A**2) NULL REMARK 3 B22 (A**2) NULL REMARK 3 B33 (A**2) NULL REMARK 3 B12 (A**2) NULL REMARK 3 B13 (A**2) NULL REMARK 3 B23 (A**2) NULL REMARK 3 REMARK 3 ESTIMATED COORDINATE ERROR. REMARK 3 ESD FROM LUZZATI PLOT (A) NULL REMARK 3 ΞSD FROM SIGMAA (A) NULL REMARK 3 LOW RESOLUTION CUTOFF (A) NULL REMARK 3 REMARK 3 CROSS-VALIDATED ESTIMATED COORDINATE ERROR. REMARK 3 ESD FROM C-V LUZZATI PLOT (A) : NULL REMARK 3 ESD FROM C-V SIGMAA (A) : NULL REMARK 3 REMARK 3 RMS DEVIATIONS FROM IDEAL VALUES. REMARK 3 BOND LENGTHS (A) O . O Oi REMARK 3 BOND ANGLES (DEGREES) 1.5 REMARK 3 DIHEDRAL ANGLES (DEGREES) 23.2 REMARK 3 IMPROPER ANGLES (DEGREES) 1.20 REMARK 3

I REMARK 3 ISOTROPIC THERMAL MODEL : RESTRAINED

REMARK 3

REMARK 3 ISOTROPIC THERMAL FACTOR RESTRAINTS. RMS SIGMA

REMARK 3 MAIN-CHAIN BOND (A**2) 1.46 1.0

REMARK 3 MAIN-CHAIN ANGLE (A**2) 2.16 1.5

REMARK 3 SIDE-CHAIN BOND (A**2) 2.87 1.5

REMARK 3 SIDE-CHAIN ANGLE (A**2) 4.35 2.0

REMARK 3

REMARK 3 NCS MODEL : NULL

REMARK 3

REMARK 3 NCS RESTRAINTS. RMS SIGMA/WEIGHT

REMARK 3 GROUP 1 POSITIONAL (A) NULL NULL

REMARK 3 GROUP 1 B-FACTOR (A**2) NULL NULL

REMARK 3

REMARK 3 PARAMETER FILE 1 PARAMCSDX_MOD . PRO

REMARK 3 PARAMETER FILE 2 PARAM19.SOL

REMARK 3 PARAMETER FILE 3 PARAMCSDX.MISC

REMARK 3 PARAMETER FILE 4 PARAMll.DNA

REMARK 3 TOPOLOGY FILE 1 TOPHCSDX . PRO

REMARK 3 TOPOLOGY FILE 2 TOPH19.PEP

REMARK 3 TOPOLOGY FILE 3 MOD_TOPHll DNA

REMARK 3 TOPOLOGY FILE 4 TOPH19.SOL

REMARK 3

REMARK 3 OTHER REFINEMENT REMARKS: NULL

REMARK 4

REMARK 4 1IR3 COMPLIES WITH FORMAT V. 2.2 16-DEC-1996

REMARK 6

REMARK 6 THE FOLLOWING RESIDUES WERE NOT MODELED DUE TO POOR

REMARK 6 ELECTRON DENSITY: A 978 - A 980, B 1 - B 7, B 14 - B 18

REMARK 200

REMARK 200 EXPERIMENTAL DETAILS

REMARK 200 EXPERIMENT TYPE X-RAY DIFFRACTION

REMARK 200 DATE OF DATA COLLECTION JUN-1996

REMARK 200 TEMPERATURE (KELVIN) 120

REMARK 200 PH 7.5

REMARK 200 NUMBER OF CRYSTALS USED 1

REMARK 200

REMARK 200 SYNCHROTRON (Y/N) Y

REMARK 200 RADIATION SOURCE NSLS

REMARK 200 BΞAMLINE X4A

REMARK 200 X-RAY GENERATOR MODEL NULL

REMARK 200 MONOCHROMATIC OR LAUE (M/L) M

REMARK 200 WAVELENGTH OR RANGE (A) 0.9796

REMARK 200 MONOCHROMATOR SILICON CRYSTAL

REMARK 200 OPTICS MIRROR

REMARK 200

REMARK 200 DETECTOR TYPE IMAGE PLATE

REMARK 200 DETECTOR MANUFACTURER FUJI

REMARK 200 INTENSITY-INTEGRATION SOFTWARE DENZO

REMARK 200 DATA SCALING SOFTWARE SCALΞPACK

REMARK 200

REMARK 200 NUMBER OF UNIQUE REFLECTIONS 28286

REMARK 200 RESOLUTION RANGE HIGH (A) 1.90

REMARK 200 RESOLUTION RANGE LOW (A) 20.0

REMARK 200 REJECTION CRITERIA (SIGMA(I) ) 0.

REMARK 200

REMARK 200 OVERAL .

tf REMARK 200 COMPLETENESS FOR RANGE (%) 98.6 REMARK 200 DATA REDUNDANCY 4.1 REMARK 200 R MERGE (I) 0.065 REMARK 200 R SYM (I) 0.065 REMARK 200 <I/SIGMA(I)> FOR THE DATA SET 12.9 REMARK 200 REMARK 200 IN THE HIGHEST RESOLUTION SHELL. REMARK 200 HIGHEST RESOLUTION SHELL, RANGE HIGH (A) NULL REMARK 200 HIGHEST RESOLUTION SHELL, RANGE LOW (A) NULL REMARK 200 COMPLETENESS FOR SHELL (%) NULL REMARK 200 DATA REDUNDANCY IN SHELL NULL REMARK 200 R MERGE FOR SHELL (I) NULL REMARK 200 R SYM FOR SHELL (I) NULL REMARK 200 <I/SIGMA(I)> FOR SHELL NULL REMARK 200 REMARK 200 METHOD USED TO DETERMINE THE STRUCTURE: MOLECULAR REMARK 200 REPLACEMENT REMARK 200 SOFTWARE USED: AMORE REMARK 200 STARTING MODEL: PDB ENTRY lIRK REMARK 200 REMARK 200 REMARK: NULL REMARK 280 REMARK 280 CRYSTAL REMARK 280 SOLVENT CONTENT, VS (%): 50. REMARK 280 MATTHEWS COEFFICIENT, VM (ANGSTROMS* * 3 /DA) : 2.4 REMARK 280 REMARK 280 CRYSTALLIZATION CONDITIONS: 22% PEG 8000, 100 MM TRIS-HCL, REMARK 280 PH 7.5, 2% ETHYLENE GLYCOL REMARK 290 REMARK 290 CRYSTALLOGRAPHIC SYMMETRY REMARK 290 SYMMETRY OPERATORS FOR SPACE GROUP: P 32 2 1 REMARK 290 REMARK 290 SYMOP SYMMETRY REMARK 290 NNNMMM OPERATOR REMARK 290 1555 X,Y,Z REMARK 290 2555 -Y,X-Y,Z+2/3 REMARK 290 3555 Y-X,-X,Z+l/3 REMARK 290 4555 Y,X,-Z REMARK 290 5555 X-Y,-Y,l/3-Z REMARK 290 6555 -X,Y-X,2/3-Z REMARK 290 REMARK 290 WHERE NNN -> OPERATOR NUMBER REMARK 290 MMM -> TRANSLATION VECTOR REMARK 290 REMARK 290 CRYSTALLOGRAPHIC SYMMETRY TRANSFORMATIONS REMARK 290 THE FOLLOWING TRANSFORMATIONS OPERATE ON THE ATOM/HETATM REMARK 290 RECORDS IN THIS ENTRY TO PRODUCE CRYSTALLOGRAPHICALLY REMARK 290 RELATED MOLECULES. REMARK 290 SMTRY1 1 1.000000 0.000000 0 000000 0 00000 REMARK 290 SMTRY2 1 0.000000 1.000000 0 000000 0 00000 REMARK 290 SMTRY3 1 0.000000 0.000000 1 000000 0 00000 REMARK 290 SMTRY1 2 -0.499971 -0.866071 0 000000 0 00000 REMARK 290 SMTRY2 2 0.865979 -0.500029 0 000000 0 00000 REMARK 290 SMTRY3 2 0.000000 0.000000 1 000000 92 73427 REMARK 290 SMTRY1 3 -0.500029 0.866071 0 000000 0 00000 REMARK 290 SMTRY2 3 -0.865979 -0.499971 0 000000 0 00000 REMARK 290 SMTRY3 3 0.000000 0.000000 1 000000 46 36713 REMARK 290 SMTRY1 4 -0.499971 0..866105 0..000000 0.00000

REMARK 290 SMTRY2 4 0.865979 0 .499971 0 .000000 0 .00000

REMARK 290 SMTRY3 4 0.000000 0, .000000 -1. .000000 0. .00000

REMARK 290 SMTRY1 5 1.000000 -0. .000067 0. .000000 0. .00000

REMARK 290 SMTRY2 5 0.000000 -1 .000000 0, .000000 0 .00000

REMARK 290 SMTRY3 5 0.000000 0. .000000 -1. .000000 46, .36713

REMARK 290 SMTRY1 6 • -0.500029 -0, .866038 0. .000000 0 .00000

REMARK 290 SMTRY2 6 -0.865979 0. .500029 0, .000000 0, .00000

REMARK 290 SMTRY3 6 0.000000 0, .000000 -1. .000000 92. .73427

REMARK 290

REMARK 290 REMARK: NULL

REMARK 470

REMARK 470 MISSING ATOM

REMARK 470 THE FOLLOWING RESIDUES HAVE MISSING ATOMS 1 [M=MODEL NUMBER;

REMARK 470 RES=RΞSIDUE NAME; C=CHAIN IDENTIFIER; SSEQ= =SEQUENCE NUMBER;

REMARK 470 I=INSΞRTION CODE) :

REMARK 470 M RES CSSEQI ATOMS

REMARK 470 GLU A 988 CG CD OEl OE2

REMARK 470 ASN A1014 CG ODl ND2

REMARK 470 ARG A1016 CG CD NE CZ NHl NH2

REMARK 470 GLU A1024 CG CD OEl OE2

REMARK 470 GLU A1034 CG CD OEl OE2

REMARK 470 LYS A1068 CG CD CE NZ

REMARK 470 GLN A1070 CG CD OEl NE2

REMARK 470 GLU A1094 CG CD OEl OE2

REMARK 470 GLU A1096 CG CD OEl OE2

REMARK 470 LYS A1168 CG CD CE NZ

REMARK 470 ARG A1243 CG CD NE CZ NH1 NH2

REMARK 470 GLU A1280 CG CD OEl OE2

REMARK 470 LYS A1283 CG CD CE NZ

REMARK 650

REMARK 650 HELIX

REMARK 650 DETERMINATION METHOD: TAKEN FROM RELEASED PDB ENTRY

REMARK 700

REMARK 700 SHEET

REMARK 700 DETERMINATION METHOD: TAKEN FROM RELEASED PDB ENTRY

REMARK 999

REMARK 999 SEQUENCE

REMARK 999 1IR3 A SWS P P006213 1 - 1007 NOT IN ATOMS LIST

REMARK 999 1IR3 A SWS PP006213 1311 - 1382 NOT IN ATOMS LIST

DBRΞF 1IRΞ '. A 981 1283 SSWWSS P06213 INSR_HUMAN 1008 1310

DBREF 1IR3 B ! 13 P PDDB B 11IIRR33 1IR3 8 13

SEQADV 1IR3 SER A 981 S SWWSS P P0066221133 CYS 1008 ENGINEERED

SEQADV 1IR3 PHE A 984 SWS P06213 TYR 1011 ENGINEERED

SEQADV 1IR3 PTR A 1158 SWS P06213 TYR 1185 MODIFIED RESIDUE

SEQADV 1IR3 PTR A 1162 SWS P06213 TYR 1189 MODIFIED RESIDUE

SEQADV 1IR3 PTR A 1163 SWS P06213 TYR 1190 MODIFIED RESIDUE

SEQRES 1 A 306 VAL PHE PRO SER SER VAL PHE VAL PRO ASP GLU TRP GLU

SEQRES 2 A 306 VAL SER ARG GLU LYS ILΞ THR LEU LEU ARG GLU LEU GLY

SEQRES 3 A 306 GLN GLY SER PHE GLY MET VAL TYR GLU GLY ASN ALA ARG

SEQRES 4 A 306 ASP ILE ILE LYS GLY GLU ALA GLU THR ARG VAL ALA VAL

SEQRES 5 A 306 LYS THR VAL ASN GLU SER ALA SER LEU ARG GLU ARG ILE

SEQRES 6 A 306 GLU PHE LEU ASN GLU ALA SER VAL MET LYS GLY PHE THR

SEQRES 7 A 306 CYS HIS HIS VAL VAL ARG LEU LEU GLY VAL VAL SER LYS

SEQRES 8 A 306 GLY GLN PRO THR LEU VAL VAL MET GLU LEU MET ALA HIS

SEQRES 9 A 306 GLY ASP LEU LYS SER TYR LEU ARG SER LEU ARG PRO GLU

SEQRES 10 A 306 ALA GLU ASN ASN PRO GLY ARG PRO PRO PRO THR LEU GLN

*/ SEQRES 11 A 306 GLU MET ILE GLN MET ALA ALA GLU ILE ALA ASP GLY MET

SEQRES 12 A 306 ALA TYR LEU ASN ALA LYS LYS PHE VAL HIS ARG ASP LEU

SEQRES 13 A 306 ALA ALA ARG ASN CYS MET VAL ALA HIS ASP PHE THR VAL

SEQRES 14 A 306 LYS ILE GLY ASP PHE GLY MET THR ARG ASP ILE PTR GLU

SEQRES 15 A 306 THR ASP PTR PTR ARG LYS GLY GLY LYS GLY LEU LEU PRO

SEQRES 16 A 306 VAL ARG TRP MET ALA PRO GLU SER LEU LYS ASP GLY VAL

SEQRES 17 A 306 PHE THR THR SER SER ASP MET TRP SER PHE GLY VAL VAL

SEQRES 18 A 306 LEU TRP GLU ILE THR SER LEU ALA GLU GLN PRO TYR GLN

SEQRES 19 A 306 GLY LEU SER ASN GLU GLN VAL LEU LYS PHE VAL MET ASP

SEQRES 20 A 306 GLY GLY TYR LEU ASP GLN PRO ASP ASN CYS PRO GLU ARG

SEQRES 21 A 306 VAL THR ASP LEU MET ARG MET CYS TRP GLN PHE ASN PRO

SEQRES 22 A 306 LYS MET ARG PRO THR PHE LEU GLU ILE VAL ASN LEU LEU

SEQRES 23 A 306 LYS ASP ASP LEU HIS PRO SER PHE PRO GLU VAL SER PHE

SEQRES 24 A 306 PHE HIS SER GLU GLU ASN LYS

SEQRES I B 18 LYS LYS LYS LEU PRO ALA THR GLY ASP TYR MET ASN MET

SEQRES 2 B 18 SER PRO VAL GLY ASP

M0DRES 1IR3 PTR A 1158 TYR PHOSPHOTYROSINΞ

MODRES 1IR3 PTR A 1162 TYR PHOSPHOTYROSINΞ

MODRES 1IR3 PTR A 1163 TYR PHOSPHOTYROSINE

HET PTR A1158 16

HET PTR All62 16

HET PTR All63 16

HET ANP 300 31

HET MG 301 1

HET MG 3 30022 1

HETNAM PTR PHOSPHOTYROSINE

HETNAM ANP 5 ' -ADENYLY-IMIDO TRIPHOSPHATE

HETNAM MG MAGNESIUM ION

HETSYN PTR PHOSPHONOTYROSINE

HETSYN ANP AMP-PNP

FORMUL PTR 3 (C9 H12 Nl 06 PI)

FORMUL ANP CIO H17 N6 012 P3

FORMUL MG 2 (MG1 2+)

FORMUL HOH *202 (H2 Ol)

HELIX 1 SER A 982 PHE 984 5 3

HELIX 2 SER A 992 GLU 994 5 3

HELIX C LEU A 1038 L LYYSS A 1052 1 15

HELIX D LEU A 1084 S SEERR A 1090 1 7

HELIX E LEU A 1106 A ALLAA A 1125 1 20

HELIX 3 ALA A 1134 A ARRGG A 1136 5 3

HELIX 4 VAL A 1173 TRP A 1175 5 3

HELIX EF PRO A 1178 ASP A 1183 1 6

HELIX 9 F THR A 1 1118888 THR A 1 1220033 1 16

HELIX 10 G ASN A 11221155 MET A 11222233 1 9

HELIX 11 H GLU A 11223366 CYS A 11224455 1 10

HELIX 12 5 PRO A 11225500 MET A 11225522 5 3

HELIX 13 I PHE A 11225566 LEU A 11226633 1

HELIX 14 J PHE A 1271 VAL A 11227744 1

SHEET 1 A 5 LEU A1062 VAL A1066 0

SHEET 2 A LEU A1073 GLU A1077 -1 N VAL A1075 O LEU A1063

SHEET 3 A GLU A1022 THR A1031 -1 N LYS A1030 O VAL A1074

SHEET 4 A MET A1009 ILE A1019 -1 N ALA A1015 O THR A1025

SHEET 5 A ILE A 996 GLN A1004 -1 N ARG A1000 O GLU A1012

SHEET 1 B CYS A1138 VAL A1140 0

SHEET 2 B VAL A1146 ILE A1148 -1 N LYS A1147 O MET A1139

SHEET 1 C PHE A1128 VAL A1129 0

SHEET 2 C ARG A1155 ASP A1156 -1 N ARG A1155 O VAL A1129

3 SHEET 1 D 2 PTR A1163 ARG A1164 0

SHEET 2 D 2 VAL A1185 PHE A1186 - -1 N PHE A1186 O PTR A1163

SHEET 1 E 2 GLY All69 LEU A1171 0

SHEET 2 E 2 MET B 11 MET B 13 - -1 N MET B 11 O ] L,EU A1171

LINK N PTR A1158 C ILE A1157

LINK C PTR A1158 N GLU A1159

LINK N PTR A1162 C ASP A1161

LINK C PTR A1162 N PTR A1163

LINK C PTR All63 N ARG All64

LINK 02G ANP 300 MG MG 301

LINK 02B ANP 300 MG MG 301

LINK MG MG 301 ODl ASN A1137

LINK MG MG 301 OD2 ASP A1150

CISPΞP 1 GLN A 1070 PRO A 1071 0 -1 0.33

CRYST1 66. ,505 66.505 139.095 90.00 90.00 120.00 : P 32 : 2 1 6

ORIGX1 1.000000 ( 3.000000 0.000000 0.00000

ORIGX2 0.000000 1.000000 0.000000 0.00000

ORIGX3 0.000000 ( 3.000000 1.000000 0.00000

SCALE1 0.015036 ( 3.008681 0.000000 0.00000

SCALE2 0.000000 ( 3.017363 0.000000 . 0.00000

SCALE3 0.000000 ( 3.000000 0.007189 0.00000

ATOM 1 N SER A 981 -59.784 29.018 -6.455 1.00 50 .08 N

ATOM 2 CA SER A 981 -58.563 28.226 -6.542 1.00 48 .57 C

ATOM 3 C SER A 981 -57.358 28.897 -5.883 1.00 48 .01 C

ATOM 4 O SER A 981 -57.185 30.116 -5.947 1.00 47 .78 0

ATOM 5 CB SER A 981 -58.233 27.897 -8.002 1.00 48 .43 c

ATOM 6 OG SER A 981 -57.020 27.164 -8.103 1.00 45 .80 0

ATOM 7 N SER A 982 -56.530 28.069 -5.257 1.00 47 .00 N

ATOM 8 CA SER A 982 -55.316 28.495 -4.564 1.00 44 .96 C

ATOM 9 C SER A 982 -54.395 29.363 -5.438 1.00 42 .72 C

ATOM 10 O SER A 982 -53.683 30.233 -4.934 1.00 41, .13 O

ATOM 11 CB SER A 982 -54.567 27.245 -4.084 1.00 47 .03 C

ATOM 12 OG SER A 982 -53.492 27.561 -3.224 1.00 50 .07 O

ATOM 13 N VAL A 983 -54.432 29.120 -6.748 1.00 39 .92 N

ATOM 14 CA VAL A 983 -53.608 29.840 -7.727 1.00 37, .38 C

ATOM 15 C VAL A 983 -53.783 31.363 -7.711 1.00 35, .53 C

ATOM 16 O VAL A 983 -52.852 32.115 -8.022 1.00 32, .65 O

ATOM 17 CB VAL A 983 -53.910 29.365 -9.175 1.00 38, .07 C

ATOM 18 CGI VAL A 983 -52.726 29.655 -10.081 1.00 36, .50 C

ATOM 19 CG2 VAL A 983 -54.260 27.894 -9.199 1.00 39, .08 C

ATOM 20 N PHE A 984 -54.978 31.811 -7.344 1.00 34, .39 N

ATOM 21 CA PHE A 984 -55.278 33.232 -7.318 1.00 33. .90 C

ATOM 22 C PHE A 984 -54.718 33.993 -6.122 1.00 34. .28 C

ATOM 23 O PHE A 984 -54.913 35.201 -6.003 1.00 35, .14 O

ATOM 24 CB PHE A 984 -56.782 33.437 -7.492 1.00 32. .80 C

ATOM 25 CG PHE A 984 -57.316 32.823 -8.761 1.00 32. .13 C

ATOM 26 CDl PHE A 984 -56.850 33.255 -10.004 1.00 31. .41 C

ATOM 27 CD2 PHE A 984 -58.239 31.779 -8.717 1.00 32. .19 C

ATOM 28 CE1 PHE A 984 -57.293 32.655 -11.187 1.00 28. .67 C

ATOM 29 CE2 PHE A 984 -58.688 31.172 -9.895 1.00 29. .61 c

ATOM 30 CZ PHE A 984 -58.211 31.613 -11.131 1.00 29. .49 c

ATOM 31 N VAL A 985 -54.024 33.284 -5.236 1.00 33. .92 N

ATOM 32 CA VAL A 985 -53.398 33.917 -4.079 1.00 34. .31 c

ATOM 33 C VAL A 985 -52.019 33.294 -3.932 1.00 35. ,82 c

ATOM 34 O VAL A 985 -51.812 32.381 -3.123 1.00 37. .61 0

ATOM 35 CB VAL A 985 -54.192 33.721 -2.773 1.00 34. .21 c

ATOM 36 CGI VAL A 985 -53.503 34.487 -1.651 1.00 37. .26 c ATOM 37 CG2 VAL A 985 -55.621 34.219 -2.931 1.00 34.06 C

ATOM 38 N PRO A 986 -51 .057 33 .772 -4 .736 1 .00 35 .32 N

ATOM 39 CA PRO A 986 -49 .680 33 .283 -4 .732 1 .00 34 .59 C

ATOM 40 C PRO A 986 -48 .782 33 .969 -3 .722 1 .00 34 .12 C

ATOM 41 O PRO A 986 -49 .136 34 .981 -3 .109 1 .00 33 .49 O

ATOM 42 CB PRO A 986 -49 .185 33 .607 -6 .148 1 .00 35 .49 C

ATOM 43 CG PRO A 986 -50 .353 34 .289 -6 .842 1 .00 36 .16 C

ATOM 44 CD PRO A 986 -51 .217 34 .815 -5 .753 1. .00 34 .81 C

ATOM 45 N ASP A 987 -47 .602 33 .386 -3 .572 1 .00 32 .04 N

ATOM 46 CA ASP A 987 -46 .583 33 .899 -2 .689 1 .00 29 .36 C

ATOM 47 C ASP A 987 -45 .579 34 .525 -3 .638 1 .00 28 .61 C

ATOM 48 O ASP A 987 -45 .015 33 .840 -4 .492 1 .00 26 .44 0

ATOM 49 CB ASP A 987 -45 .938 32 .750 -1 .919 1 .00 30 .33 c

ATOM 50 CG ASP A 987 -45 .092 33 .228 -0 .767 1, .00 30 .03 c

ATOM 51 ODl ASP A 987 -44 .384 34 .248 -0 .921 1 .00 30 .51 0

ATOM 52 OD2 ASP A 987 -45 .142 32 .579 0 .295 1 .00 32 .42 0

ATOM 53 N GLU A 988 -45 .371 35 .830 -3 .484 1, .00 28 .57 N

ATOM 54 CA GLU A 988 -44 .449 36 .588 -4. .323 1 .00 26 .71 C

ATOM 55 C GLU A 988 -43, .000 36 .117 -4 .243 1, .00 26 .31 C

ATOM 56 O GLU A 988 -42 .230 36 .320 -5 .180 1, .00 25 .97 O

ATOM 57 CB GLU A 988 -44 .516 38 .074 -3 .963 1, .00 27 .80 c

ATOM 58 N TRP A 989 -42, .631 35 .497 -3 .127 1, .00 25 .39 N

ATOM 59 CA TRP A 989 -41, .267 35 .008 -2 .942 1, .00 27 .27 C

ATOM 60 C TRP A 989 -41 .016 33 .637 -3 .562 1, .00 27 .01 C

ATOM 61 O TRP A 989 -39, .871 33 .198 -3 .649 1, .00 25 .92 O

ATOM 62 CB TRP A 989 -40, .912 34 .974 -1 .454 1, .00 27 .35 C

ATOM 63 CG TRP A 989 -40, .714 36, .331 -0, .863 1. ,00 28, .27 C

ATOM 64 CDl TRP A 989 -41, .646 37, .085 -0, .203 1. .00 28, .05 C

ATOM 65 CD2 TRP A 989 -39, .505 37 .096 -0 .868 1, .00 27 .12 c

ATOM 66 NE1 TRP A 989 -41. .088 38, .271 0, .208 1, .00 25, .74 N

ATOM 67 CE2 TRP A 989 -39, .775 38, .307 -0, .182 1. .00 28, .81 c

ATOM 68 CΞ3 TRP A 989 -38, .216 36 .881 -1, .374 1, .00 27, .43 C

ATOM 69 CZ2 TRP A 989 -38. .805 39, .298 0, .001 1. .00 27, .27 C

ATOM 70 CZ3 TRP A 989 -37. .250 37, .867 -1, .193 1. .00 27, .54 C

ATOM 71 CH2 TRP A 989 -37, .552 39, .061 -0, .505 1. .00 28, .84 C

ATOM 72 N GLU A 990 -42. .088 32, .972 -3. .987 1. ,00 26. .63 N

ATOM 73 CA GLU A 990 -42. .000 31, .649 -4, .594 1. .00 27, .13 C

ATOM 74 C GLU A 990 -41. .160 31, .631 -5. .869 1. ,00 24. .55 C

ATOM 75 O GLU A 990 -41. .332 32, .470 -6. .759 1. .00 23. .81 0

ATOM 76 CB GLU A 990 -43. .406 31, .112 -4, .897 1. .00 31, .29 c

ATOM 77 CG GLU A 990 -43. .442 29. .669 -5. .388 1. ,00 38. .10 c

ATOM 78 CD GLU A 990 -42. .906 28, .681 -4. .366 1. ,00 43. .61 c

ATOM 79 OEl GLU A 990 -42. .900 29, .014 -3, .161 1. .00 45, .63 O

ATOM 80 OE2 GLU A 990 -42. ,486 27. .572 -4. .767 1. ,00 48. .77 0

ATOM 81 N VAL A 991 -40. .246 30, .667 -5. .941 1. ,00 22, .41 N

ATOM 82 CA VAL A 991 -39. .377 30, .501 -7, .098 1. .00 21, .82 c

ATOM 83 C VAL A 991 -39. .546 29. .081 -7. .612 1. .00 20. .59 c

ATOM 84 O VAL A 991 -39. .660 28, .146 -6. .830 1. ,00 18. .85 0

ATOM 85 CB VAL A 991 -37. ,877 30. .730 -6. .738 1. ,00 22. .69 c

ATOM 86 CGI VAL A 991 -36. .978 30. .291 -7. .888 1. ,00 25. .56 c

ATOM 87 CG2 VAL A 991 -37. .626 32, .201 -6. .435 1. ,00 24. .22 c

ATOM 88 N SER A 992 -39. ,568 28. .933 -8. .931 1. ,00 22. .61 N

ATOM 89 CA SER A 992 -39. .711 27. .627 -9. .554 1. ,00 24. .47 C

ATOM 90 C SER A 992 -38. .421 26, .828 -9. .371 1. ,00 23. .24 C

ATOM 91 O SER A 992 -37. ,333 27. .325 -9. .661 1. ,00 20. .77 0

ATOM 92 CB SER A 992 -40. .007 27. .793 -11. ,042 1. 00 25. .46 c

ATOM 93 OG SER A 992 -40. ,345 26. .546 -11. ,618 1. 00 34. ,04 0

iψ ATOM 94 N ARG A 993 -38.559 25.596 -8.890 1.00 24.29 N

ATOM 95 CA ARG A 993 -37 .426 24 .696 -8 .654 1 .00 24 .91 C

ATOM 96 C ARG A 993 -36 .589 24 .486 -9 .916 1 .00 24 .75 C

ATOM 97 O ARG A 993 -35 .379 24 .278 -9 .844 1 .00 26 .44 0

ATOM 98 CB ARG A 993 -37 .942 23 .348 -8 .134 1 .00 26 .00 c

ATOM 99 CG ARG A 993 -36 .855 22 .422 -7 .599 1 .00 24 .84 c

ATOM 100 CD ARG A 993 -37 .447 21 .137 -7 .046 1 .00 23 .79 c

ATOM 101 NE ARG A 993 -38 .402 21 .365 -5 .964 1 .00 22 .54 N

ATOM 102 CZ ARG A 993 -38 .073 21 .586 -4 .694 1 .00 24 .01 c

ATOM 103 NHl ARG A 993 -36 .799 21 .615 -4 .318 1 .00 27 .70 N

ATOM 104 NH2 ARG A 993 -39 .023 21 .776 -3 .792 1 .00 28 .02 N

ATOM 105 N GLU A 994 -37 .261 24 .551 -11 .065 1 .00 25 .86 N

ATOM 106 CA GLU A 994 -36 .659 24 .392 -12 .388 1, .00 25 .91 C

ATOM 107 C GLU A 994 -35 .547 25 .408 -12 .669 1, .00 24 .31 C

ATOM 108 O GLU A 994 -34, .646 25 .155 -13, .467 1, .00 23 .81 O

ATOM 109 CB GLU A 994 -37 .742 24 .597 -13 .454 1, .00 32 .03 C

ATOM 110 CG GLU A 994 -38 .230 26 .050 -13 .508 1, .00 40 .53 C

ATOM 111 CD GLU A 994 -39, .163 26 .365 -14, .664 1, .00 45 .54 C

ATOM 112 OEl GLU A 994 -40, .366 26 .031 -14, .577 1, .00 48 .40 O

ATOM 113 OE2 GLU A 994 -38 .692 26 .970 -15 .651 1, .00 47 .94 O

ATOM 114 N LYS A 995 -35, .629 26 .565 -12, .023 1. .00 22 .05 N

ATOM 115 CA LYS A 995 -34, .658 27 .630 -12, .226 1. .00 20 .58 C

ATOM 116 C LYS A 995 -33, .373 27 .475 -11, .423 1, .00 17 .90 C

ATOM 117 O LYS A 995 -32, .393 28 .166 -11, .687 1. .00 17, .02 O

ATOM 118 CB LYS A 995 -35, .307 28 .974 -11, .882 1. .00 22, .54 C

ATOM 119 CG LYS A 995 -36, .353 29 .423 -12, .880 1. .00 26 .35 C

ATOM 120 CD LYS A 995 -37. .064 30, .673 -12, .404 1. .00 28, .09 C

ATOM 121 CE LYS A 995 -37, .569 31 .484 -13, .577 1. .00 30, .31 C

ATOM 122 NZ LYS A 995 -38, .338 32 .657 -13, .102 1. .00 34, .57 N

ATOM 123 N ILE A 996 -33. .387 26, .574 -10. .447 1. ,00 17, .09 N

ATOM 124 CA ILE A 996 -32. .236 26, .363 -9, .581 1. .00 16, .70 C

ATOM 125 C ILE A 996 -31, .374 25 .169 -9, .979 1. .00 19, .07 C

ATOM 126 O ILE A 996 -31. .887 24, .098 -10. .314 1. ,00 18. .61 0

ATOM 127 CB ILE A 996 -32. .679 26, .165 -8, .116 1. .00 15. .00 c

ATOM 128 CGI ILE A 996 -33. .625 27, .289 -7, .690 1. .00 14, .04 c

ATOM 129 CG2 ILE A 996 -31. .465 26. .108 -7. .195 1. ,00 13. .68 c

ATOM 130 CDl ILE A 996 -33. .030 28, .674 -7. .849 1. ,00 14. .23 c

ATOM 131 N THR A 997 -30. .063 25, .379 -9. .931 1. .00 17. .55 N

ATOM 132 CA THR A 997 -29. ,076 24. .347 -10. ,234 1. 00 16. ,81 c

ATOM 133 C THR A 997 -28. .045 24. .392 -9. .103 1. ,00 15. .57 c

ATOM 134 O THR A 997 -27. .478 25, .443 -8. .827 1. .00 16. .61 0

ATOM 135 CB THR A 997 -28. ,351 24. .628 -11. ,556 1. 00 16. ,04 c

ATOM 136 OG1 THR A 997 -29. .301 24. .622 -12. .626 1. ,00 18. ,26 0

ATOM 137 CG2 THR A 997 -27. .289 23, .556 -11. .813 1. ,00 17. .63 c

ATOM 138 N LEU A 998 -27. ,828 23. .257 -8. ,445 1. 00 16. ,50 N

ATOM 139 CA LEU A 998 -26. ,865 23. .157 -7. .345 1. ,00 16. ,83 c

ATOM 140 C LEU A 998 -25. .504 22. ,657 -7. ,844 1. 00 17. ,84 c

ATOM 141 O LEU A 998 -25. ,413 21. .679 -8. .592 1. 00 16. ,61 0

ATOM 142 CB LEU A 998 -27. .417 22. .259 -6. .235 1. ,00 17. ,58 c

ATOM 143 CG LEU A 998 -28. ,277 22. ,925 -5. ,150 1. 00 22. ,65 c

ATOM 144 CDl LEU A 998 -28. ,961 24. .181 -5. .664 1. 00 21. ,85 c

ATOM 145 CD2 LEU A 998 -29. ,279 21. .934 -4. .570 1. ,00 21. ,40 c

ATOM 146 N LEU A 999 -24. ,453 23. .346 -7. ,416 1. 00 15. 23 N

ATOM 147 CA LEU A 999 -23. ,085 23. .051 -7. ,832 1. 00 15. ,64 C

ATOM 148 C LEU A 999 -22. .227 22. .355 -6. ,798 1. 00 13. ,70 C

ATOM 149 O LEU A 999 -21. ,571 21. ,357 -7. ,092 1. 00 14. 25 0

ATOM 150 CB LEU A 999 -22. ,382 24. .354 -8. ,233 1. 00 17. 96 c

3^ ATOM 151 CG LEU A 999 -22.967 25.126 -9.412 1.00 16.75 C

ATOM 152 CDl LEU A 999 -22 .318 26 .502 -9 .482 1 .00 17 .11 C

ATOM 153 CD2 LEU A 999 -22 .742 24 .336 -10 .696 1, .00 16 .10 C

ATOM 154 N ARG A1000 -22 .218 22 .885 -5 .583 1 .00 13 .06 N

ATOM 155 CA ARG A1000 -21 .386 22 .303 -4 .546 1 .00 14 .13 C

ATOM 156 C ARG A1000 -21 .806 22 .744 -3 .162 1 .00 1 .21 C

ATOM 157 O ARG A1000 -22 .556 23 .701 -2 .996 1 .00 12 .42 O

ATOM 158 CB ARG A1000 -19 .913 22 .672 -4 .781 1, .00 16, .36 C

ATOM 159 CG ARG A1000 -19 .626 24 .172 -4. .735 1 .00 19 .61 C

ATOM 160 CD ARG A1000 -18 .167 24 .477 -5 .050 1 .00 22 .87 C

ATOM 161 NE ARG A1000 -17 .255 23 .902 -4 .062 1, .00 29, .29 N

ATOM 162 CZ ARG A1000 -16 .453 22 .864 -4 .289 1 .00 33 .23 C

ATOM 163 NH1 ARG A1000 -16 .444 22 .270 -5 .480 1 .00 32 .48 N

ATOM 164 NH2 ARG A1000 -15 .658 22 .416 -3 .322 1, .00 34, .72 N

ATOM 165 N GLU A1001 -21 .304 22 .027 -2 .169 1, .00 13 .88 N

ATOM 166 CA GLU A1001 -21 .598 22 .307 -0 .787 1 .00 16 .03 C

ATOM 167 C GLU A1001 -20 .741 23 .474 -0, .313 1, .00 18, .54 C

ATOM 168 O GLU A1001 -19 .517 23 .488 -0 .500 1, .00 19, .16 O

ATOM 169 CB GLU A1001 -21 .318 21 .056 0, .040 1, .00 19, .62 C

ATOM 170 CG GLU A1001 -21 .460 21 .246 1 .524 1, .00 27 .16 C

ATOM 171 CD GLU A1001 -21 .189 19 .974 2 .310 1 .00 30 .52 C

ATOM 172 OEl GLU A1001 -21 .496 18 .872 1, .800 1, .00 27, .36 O

ATOM 173 OE2 GLU A1001 -20 .691 20 .089 3 .452 1 .00 33, .15 O

ATOM 174 N LEU A1002 -21 .399 24 .462 0 .282 1 .00 18 .84 N

ATOM 175 CA LEU A1002 -20 .724 25 .635 0, .820 1, .00 19, .21 C

ATOM 176 C LEU A1002 -20 .503 25 .392 2 .301 1, .00 21, .10 C

ATOM 177 O LEU A1002 -19, .504 25, .808 2, .866 1, .00 19, .39 O

ATOM 178 CB LEU A1002 -21, .581 26 .889 0, .641 1. .00 18, .99 C

ATOM 179 CG LEU A1002 -21 .605 27 .529 -0, .741 1, .00 20, .65 c

ATOM 180 CDl LEU A1002 -22, .666 28, .610 -0, .765 1. .00 20. .51 c

ATOM 181 CD2 LEU A1002 -20, .243 28 .110 -1, .072 1. .00 23. .38 c

ATOM 182 N GLY A1003 -21 .447 24 .712 2, .931 1, .00 22, .24 N

ATOM 183 CA GLY A1003 -21, .305 24, .432 4, .342 1. .00 24, .10 C

ATOM 184 C GLY A1003 -22, .484 23, .664 4, .878 1, .00 25, .41 C

ATOM 185 O GLY A1003 -23, .503 23, .506 4, .210 1, .00 25, .96 O

ATOM 186 N GLN A1004 -22, .338 23, .189 6, .103 1. .00 25. .61 N

ATOM 187 CA GLN A1004 -23, .382 22, .433 6, .746 1, .00 26, .05 C

ATOM 188 C GLN A1004 -23. .817 23, .157 8. .005 1. .00 25. .33 C

ATOM 189 O GLN A1004 -22, .990 23, .505 8. ,851 1. .00 26. .50 0

ATOM 190 CB GLN A1004 -22, .867 21, .037 7, .070 1. .00 28, .98 C

ATOM 191 CG GLN A1004 -23. .932 20, .090 7. .564 1. .00 35. .30 c

ATOM 192 CD GLN A1004 -23. .436 18, .671 7. ,569 1. .00 40. .36 c

ATOM 193 OEl GLN A1004 -22, .493 18, .337 8, .287 1. .00 42. .84 0

ATOM 194 NE2 GLN A1004 -24. .049 17, .826 6. ,749 1. .00 44. .07 N

ATOM 195 N GLY A1005 -25. .118 23, .398 8. .115 1. .00 21. .77 N

ATOM 196 CA GLY A1005 -25, .647 24, .064 9. .287 1. .00 21, .81 C

ATOM 197 C GLY A1005 -26, .036 22, .999 10. .286 1. .00 23. .18 C

ATOM 198 O GLY A1005 -25. .836 21, .810 10. ,033 1. .00 24. .46 O

ATOM 199 N SER A1006 -26. .596 23. .409 11. ,416 1. ,00 23. .58 N

ATOM 200 CA SER A1006 -27. .020 22. .463 12. .442 1. ,00 24. ,97 C

ATOM 201 C SER A1006 -28, .172 21, .544 11. .997 1. .00 23. .97 C

ATOM 202 O SER A1006 -28. .267 20. .404 12. .449 1. .00 26. ,00 O

ATOM 203 CB SER A1006 -27. .409 23, .215 13. .719 1. .00 26. .90 C

ATOM 204 OG SER A1006 -28, .412 24, .190 13. .468 1. .00 31. .92 O

ATOM 205 N PHE A1007 -29. .037 22. .033 11. .114 1. .00 23. .39 N

ATOM 206 CA PHE A1007 -30. .180 21, .246 10. .651 1. .00 23. .56 C

ATOM 207 C PHE A1007 -30. .416 21. ,314 9. ,149 1. ,00 21. .68 C

? ^> ATOM 208 O PHE A1007 -31.535 21.089 8.683 1.00 21.01 0

ATOM 209 CB PHE A1007 -31 .458 21 .681 11 .386 1 .00 26 .48 C

ATOM 210 CG PHE A1007 -31 .749 23 .160 11 .294 1 .00 28 .63 C

ATOM 211 CDl PHE A1007 -32 .378 23 .697 10 .173 1 .00 30 .16 C

ATOM 212 CD2 PHE A1007 -31 .384 24 .014 12 .329 1 .00 30 .53 C

ATOM 213 CE1 PHE A1007 -32 .639 25 .064 10 .083 1 .00 34 .25 C

ATOM 214 CE2 PHE A1007 -31 .639 25 .380 12 .251 1 .00 31 .63 C

ATOM 215 CZ PHE A1007 -32 .268 25 .908 11 .125 1 .00 31 .76 C

ATOM 216 N GLY A1008 -29 .369 21 .615 8 .390 1 .00 20 .32 N

ATOM 217 CA GLY A1008 -29 .515 21 .696 6 .949 1 .00 19 .43 C

ATOM 218 C GLY A1008 -28 .192 21 .852 6 .230 1 .00 21 .09 C

ATOM 219 O GLY A1008 -27. .124 21 .858 6 .857 1 .00 18 .56 0

ATOM 220 N MET A1009 -28 .273 22 .024 4 .915 1 .00 19 .41 N

ATOM 221 CA MET A1009 -27, .097 22 .181 4 .070 1. .00 20 .24 C

ATOM 222 C MET A1009 -27, .188 23 .462 3 .263 1 .00 18 .53 C

ATOM 223 O MET A1009 -28 .271 23 .855 2 .844 1 .00 17 .59 0

ATOM 224 CB MET A1009 -26, .995 21 .007 3 .089 1 .00 23 .87 C

ATOM 225 CG MET A1009 -26, .575 19 .667 3 .692 1, .00 32 .72 C

ATOM 226 SD MET A1009 -24, .861 19 .650 4 .280 1 .00 39 .56 S

ATOM 227 CE MET A1009 -24, .152 20 .860 3 .183 1 .00 30 .51 C

ATOM 228 N VAL A1010 -26, .051 24 .115 3 .057 1 .00 15 .93 N

ATOM 229 CA VAL A1010 -26, .011 25 .323 2. .238 1 .00 15 .22 C

ATOM 230 C VAL A1010 -25, .189 24 .962 1 .005 1, .00 14 .68 C

ATOM 231 O VAL A1010 -24, .054 24 .480 1 .130 1 .00 15 .01 0

ATOM 232 CB VAL A1010 -25, .370 26 .528 2 .969 1 .00 15 .64 C

ATOM 233 CGI VAL A1010 -25, .359 27 .752 2. .048 1 .00 11 .95 C

ATOM 234 CG2 VAL A1010 -26. .134 26 .834 4, .258 1, .00 13, .15 C

ATOM 235 N TYR A1011 -25, .769 25 .180 -0 .175 1, .00 14, .15 N

ATOM 236 CA TYR A1011 -25, .114 24 .873 -1, .445 1, .00 13, .07 C

ATOM 237 C TYR A1011 -24. .916 26, .109 -2, .300 1. ,00 14. .55 C

ATOM 238 O TYR A1011 -25. .736 27, .023 -2, .279 1. .00 12, .35 0

ATOM 239 CB TYR A1011 -25. .980 23 .918 -2, .289 1, .00 13, .49 c

ATOM 240 CG TYR A1011 -26. ,314 22, .588 -1, ,656 1. .00 13. .25 c

ATOM 241 CDl TYR A1011 -25. .468 21, .491 -1, .808 1. ,00 15. .24 c

ATOM 242 CD2 TYR A1011 -27. .488 22, .421 -0. .917 1. ,00 14. .62 c

ATOM 243 CE1 TYR A1011 -25. ,779 20, .252 -1. .233 1. ,00 17. .75 c

ATOM 244 CE2 TYR A1011 -27. ,815 21, .186 -0, .346 1. .00 14. ,79 c

ATOM 245 CZ TYR A1011 -26. .954 20, .107 -0, .506 1. .00 19. .16 c

ATOM 246 OH TYR A1011 -27. ,265 18. ,891 0. .066 1. .00 19. .62 0

ATOM 247 N GLU A1012 -23. ,826 26. .134 -3. .056 1. .00 12. .91 N

ATOM 248 CA GLU A1012 -23. .604 27, ,210 -4. .006 1. .00 14. ,34 C

ATOM 249 C GLU A1012 -24. ,392 26. ,736 -5. .229 1. ,00 14. .07 C

ATOM 250 O GLU A1012 -24. ,394 25. .547 -5. .550 1. ,00 13. ,48 0

ATOM 251 CB GLU A1012 -22. ,135 27. .322 -4. .410 1. ,00 15. .28 c

ATOM 252 CG GLU A1012 -21. ,937 28. .273 -5. .602 1. ,00 18. ,92 c

ATOM 253 CD GLU A1012 -20. ,527 28. .261 -6. ,176 1. ,00 22. .91 c

ATOM 254 OEl GLU A1012 -19. ,621 27, .669 -5. .555 1. ,00 28. .70 0

ATOM 255 OΞ2 GLU A1012 -20. ,328 28. .845 -7. .261 1. ,00 20. ,13 0

ATOM 256 N GLY A1013 -25. ,063 27. .654 -5. .908 1. ,00 14. ,68 N

ATOM 257 CA GLY A1013 -25. ,817 27. .272 -7. .081 1. ,00 14. .14 c

ATOM 258 C GLY A1013 -25. ,910 28. .430 -8, .041 1. ,00 13. ,27 c

ATOM 259 O GLY A1013 -25. ,250 29. .457 -7. .852 1. ,00 11. ,43 0

ATOM 260 N ASN A1014 -26. ,705 28. .239 -9. ,087 1. ,00 15. .07 N

ATOM 261 CA ASN A1014 -26. .959 29, .253 -10. .104 1. ,00 18. .49 C

ATOM 262 C ASN A1014 -28. ,478 29. .238 -10. .315 1. 00 19. ,34 C

ATOM 263 O ASN A1014 -29. ,107 28. .174 -10. .336 1. ,00 20. ,80 0

ATOM 264 CB ASN A1014 -26. ,225 28. .927 -11. ,411 1. ,00 18. ,36 C

VI ATOM 265 N ALA A1015 -29.066 30.419 -10.457 1.00 17.95 N

ATOM 266 CA ALA A1015 -30 .505 30 .525 -10 .642 1 .00 16 .59 C

ATOM 267 C ALA A1015 -30 .776 31 .287 -11 .924 1 .00 18 .26 C

ATOM 268 O ALA A1015 -30 .158 32 .315 -12 .178 1 .00 18 .71 O

ATOM 269 CB ALA A1015 -31 .132 31 .236 -9 .453 1 .00 13 .25 C

ATOM 270 N ARG A1016 -31 .698 30 .779 -12 .732 1 .00 19 .38 N

ATOM 271 CA ARG A1016 -32 .039 31 .425 -13 .993 1 .00 20 .22 C

ATOM 272 C ARG A1016 -33 .236 32 .352 -13 .831 1 .00 20 .22 C

ATOM 273 O ARG A1016 -34 .262 31 .972 -13 .263 1 .00 20 .08 O

ATOM 274 CB ARG A1016 -32 .334 30 .385 -15 .077 1 .00 21 .10 C

ATOM 275 N ASP A1017 -33 .079 33 .574 -14 .329 1 .00 21 .67 N

ATOM 276 CA ASP A1017 -34 .118 34 .598 -14 .292 1 .00 23 .68 C

ATOM 277 C ASP A1017 -34 .885 34 .765 -12 .989 1 .00 23 .48 C

ATOM 278 O ASP A1017 -36 .109 34 .623 -12 .952 1 .00 23 .96 O

ATOM 279 CB ASP A1017 -35 .096 34 .411 -15 .454 1 .00 30 .04 C

ATOM 280 CG ASP A1017 -34 .449 34 .657 -16 .805 1 .00 35 .31 C

ATOM 281 OD1 ASP A1017 -33, .485 35 .448 -16 .879 1 .00 39 .38 O

ATOM 282 OD2 ASP A1017 -34, .906 34 .062 -17 .802 1 .00 43 .88 O

ATOM 283 N ILE A1018 -34 .164 35 .065 -11 .917 1 .00 22 .10 N

ATOM 284 CA ILE A1018 -34, .802 35 .305 -10 .628 1, .00 22 .44 C

ATOM 285 C ILE A1018 -34, .656 36 .781 -10 .233 1, .00 22 .39 C

ATOM 286 O ILE A1018 -35, .282 37 .245 -9 .282 1 .00 22 .37 O

ATOM 287 CB ILE A1018 -34, .252 34 .387 -9 .530 1, .00 23 .10 C

ATOM 288 CGI ILE A1018 -32, ,751 34 .615 -9 .334 1, .00 20 .39 C

ATOM 289 CG2 ILE A1018 -34, .535 32 .926 -9 .896 1 .00 24 .78 C

ATOM 290 CDl ILE A1018 -32, .241 34 .100 -8 .006 1 .00 22 .96 C

ATOM 291 N ILE A1019 -33. .827 37 .503 -10, .983 1. .00 21, .45 N

ATOM 292 CA ILE A1019 -33. .590 38 .926 -10, .778 1. ,00 21 .16 C

ATOM 293 C ILE A1019 -33, .725 39 .595 -12, .150 1, .00 21 .18 C

ATOM 294 O ILE A1019 -33. .110 39, .155 -13. .121 1. .00 19, .36 0

ATOM 295 CB ILE A1019 -32. .172 39, .203 -10, .191 1. .00 19, .70 c

ATOM 296 CGI ILE A1019 -32. .107 38, .750 -8, .727 1, .00 17, .73 c

ATOM 297 CG2 ILE A1019 -31. .832 40, .688 -10. ,285 1. .00 19, .33 c

ATOM 298 CDl ILE A1019 -30. .808 39, .094 -8, ,027 1. .00 20, ,30 c

ATOM 299 N LYS A1020 -34. .544 40, .646 -12. .230 1. .00 22, .68 N

ATOM 300 CA LYS A1020 -34. ,750 41. .368 -13. .493 1. ,00 23. .92 c

ATOM 301 C LYS A1020 -33. ,445 41. .955 -14. .003 1. .00 24, .34 C

ATOM 302 O LYS A1020 -32. .696 42, .573 -13. .251 1. ,00 26. .13 O

ATOM 303 CB LYS A1020 -35. ,791 42. .481 -13. ,329 1. ,00 24. .46 C

ATOM 304 CG LYS A1020 -37. ,219 42. .004 -13. ,387 1. ,00 23. .13 C

ATOM 305 CD LYS A1020 -38. ,179 43. .110 -12. .977 1. ,00 27. .67 c

ATOM 306 CE LYS A1020 -39. ,618 42. .633 -12. ,996 1. 00 27. .29 c

ATOM 307 NZ LYS A1020 -40. ,549 43. ,621 -12. ,376 1. ,00 28. .62 N

ATOM 308 N GLY A1021 -33. ,179 41. .761 -15. ,287 1. ,00 25. .00 N

ATOM 309 CA GLY A1021 -31. ,945 42. .264 -15. ,852 1. 00 25. ,80 C

ATOM 310 C GLY A1021 -30. ,830 41. .236 -15. ,808 1. 00 26. ,60 C

ATOM 311 O GLY A1021 -29. ,858 41. .364 -16. ,550 1. ,00 27. .91 O

ATOM 312 N GLU A1022 -30. ,950 40. ,235 -14. ,931 1. 00 25. ,57 N

ATOM 313 CA GLU A1022 -29. ,942 39. ,179 -14. ,806 1. 00 23. ,91 C

ATOM 314 C GLU A1022 -30. ,474 37. .856 -15. ,334 1. 00 22. .07 C

ATOM 315 O GLU A1022 -31. ,399 37. .281 -14. ,769 1. ,00 23. .27 O

ATOM 316 CB GLU A1022 -29. ,492 39. ,019 -13. ,350 1. 00 23. ,22 C

ATOM 317 CG GLU A1022 -28. ,723 40. .217 -12. ,818 1. 00 26. ,60 C

ATOM 318 CD GLU A1022 -28. ,180 40. .025 -11. ,410 1. 00 30. ,67 C

ATOM 319 OEl GLU A1022 -27. 901 38. ,875 -11. 008 1. 00 32. ,54 O

ATOM 320 OE2 GLU' A1022 -28. ,015 41. ,043 -10. ,703 1. 00 32. ,13 O

ATOM 321 N ALA A1023 -29. ,881 37. ,386 -16. ,426 1. 00 21. .01 N

ii ATOM 322 CA ALA A1023 -30.274 36.129 -17.051 1.00 21.86 C

ATOM 323 C ALA A1023 -30 .036 34 .969 -16 .092 1 .00 20 .42 C

ATOM 324 O ALA A1023 -30 .874 34 .073 -15 .976 1 .00 20 .75 O

ATOM 325 CB ALA A1023 -29 .502 35 .920 -18 .346 1 .00 24 .65 C

ATOM 326 N GLU A1024 -28 .889 35 .004 -15 .414 1 .00 20 .43 N

ATOM 327 CA GLU A1024 -28 .507 33 .987 -14 .432 1 .00 19 .72 C

ATOM 328 C GLU A1024 -27 .866 34 .690 -13 .240 1 .00 18 .70 C

ATOM 329 O GLU A1024 -27 .155 35 .686 -13 .409 1 .00 21 .86 O

ATOM 330 CB GLU A1024 -27 .526 32 .986 -15 .045 1 .00 21 .21 C

ATOM 331 N THR A1025 -28 .116 34 .173 -12 .038 1 .00 16 .20 N

ATOM 332 CA THR A1025 -27 .591 34 .761 -10 .812 1 .00 13 .74 C

ATOM 333 C THR A1025 -26 .970 33 .701 -9 .910 1 .00 14 .24 C

ATOM 334 O THR A1025 -27 .575 32 .654 -9 .674 1 .00 12 .98 O

ATOM 335 CB THR A1025 -28 .728 35 .459 -10 .010 1 .00 16 .74 C

ATOM 336 OG1 THR A1025 -29 .354 36 .458 -10 .827 1, .00 16 .72 O

ATOM 337 CG2 THR A1025 -28 .187 36 .122 -8 .729 1 .00 13 .41 C

ATOM 338 N ARG A1026 -25 .767 33 .981 -9 .405 1 .00 14 .76 N

ATOM 339 CA ARG A1026 -25 .073 33 .068 -8 .497 1, .00 15 .16 C

ATOM 340 C ARG A1026 -25 .796 33 .157 -7 .159 1, .00 14 .43 C

ATOM 341 O ARG A1026 -26 .103 34 .249 -6 .685 1 .00 13 .30 0

ATOM 342 CB ARG A1026 -23 .602 33 .468 -8 .346 1, .00 17 .71 c

ATOM 343 CG ARG A1026 -22 .834 33 .462 -9 .670 1, .00 20 .00 c

ATOM 344 CD ARG A1026 -21 .335 33 .649 -9 .464 1 .00 23 .97 c

ATOM 345 NE ARG A1026 -20, .735 32 .527 -8 .743 1, ,00 28 .37 N

ATOM 346 CZ ARG A1026 -19 .572 32 .580 -8 .095 1, .00 30 .06 C

ATOM 347 NHl ARG A1026 -18. .863 33 .703 -8 .070 1, .00 31 .42 N

ATOM 348 NH2 ARG A1026 -19, .133 31, .514 -7 .442 1, .00 29, .68 N

ATOM 349 N VAL A1027 -26, .074 32 .010 -6 .550 1, .00 12 .69 N

ATOM 350 CA VAL A1027 -26 .811 31 .989 -5 .292 1. .00 11 .75 C

ATOM 351 C VAL A1027 -26, .301 30, .971 -4, .290 1, .00 12, .55 C

ATOM 352 O VAL A1027 -25, .496 30, .111 -4 .609 1, ,00 14, .17 O

ATOM 353 CB VAL A1027 -28, .318 31 .640 -5 .534 1, .00 12 .96 C

ATOM 354 CGI VAL A1027 -28. .977 32, .674 -6, .427 1. .00 10, .94 C

ATOM 355 CG2 VAL A1027 -28, .450 30, .248 -6, .162 1. .00 14, .19 C

ATOM 356 N ALA A1028 -26, ,792 31, .098 -3 .065 1, .00 12, .73 N

ATOM 357 CA ALA A1028 -26. ,499 30, .169 -1, .993 1. .00 13. .56 C

ATOM 358 C ALA A1028 -27, ,898 29, .631 -1, .708 1. .00 14, .24 C

ATOM 359 O ALA A1028 -28, .864 30, .401 -1, .626 1. .00 12, ,70 O

ATOM 360 CB ALA A1028 -25. .944 30. .891 -0, .781 1. ,00 14. ,54 C

ATOM 361 N VAL A1029 -28. .014 28, .318 -1, .566 1. ,00 12, .82 N

ATOM 362 CA VAL A1029 -29, ,306 27, .702 -1, .325 1. .00 12, .87 C

ATOM 363 C VAL A1029 -29. .255 26. .868 -0, .062 1. .00 14. .20 C

ATOM 364 O VAL A1029 -28. .437 25, .954 0, .062 1. .00 11, .84 O

ATOM 365 CB VAL A1029 -29, ,717 26. .801 -2, .509 1. ,00 13, ,76 C

ATOM 366 CGI VAL A1029 -31. .093 26. .197 -2. .265 1. ,00 17. .22 C

ATOM 367 CG2 VAL A1029 -29. .698 27, .593 -3, .813 1. .00 10. .97 C

ATOM 368 N LYS A1030 -30. ,127 27. .198 0. .882 1. .00 12. .71 N

ATOM 369 CA LYS A1030 -30. ,193 26. .459 2. .124 1. .00 16. .20 C

ATOM 370 C LYS A1030 -31. ,377 25, .502 2, .126 1. ,00 17, .31 C

ATOM 371 0 LYS A1030 -32. ,472 25. .846 1. .686 1. .00 17. .09 O

ATOM 372 CB LYS A1030 -30. .292 27. .408 3, .312 1. .00 16. .06 c

ATOM 373 CG LYS A1030 -30. .527 26. .661 4, .622 1. .00 20. .55 c

ATOM 374 CD LYS A1030 -29. ,823 27. .310 5. .787 1. .00 24. ,74 c

ATOM 375 CE LYS A1030 -30. ,152 26. .579 7. .082 1. .00 25. .33 c

ATOM 376 NZ LYS A1030 -29. .560 27, .281 8, .247 1. .00 25. ,67 N

ATOM 377 N THR A1031 -31. ,150 24. .291 2. .616 1. ,00 19. ,20 N

ATOM 378 CA THR A1031 -32. ,209 23. .288 2. .702 1. .00 20. .21 C

i°l ATOM 379 C THR A1031 -32.369 22.950 4.176 1.00 21.90 C

ATOM 380 O THR A1031 -31 .529 23 .325 4 .996 1 .00 21 .59 O

ATOM 381 CB THR A1031 -31 .817 21 .981 1 .995 1 .00 21 .18 C

ATOM 382 OG1 THR A1031 -30 .698 21 .398 2 .672 1 .00 21 .83 O

ATOM 383 CG2 THR A1031 -31 .454 22 .236 0 .541 1 .00 22 .86 C

ATOM 384 N VAL A1032 -33 .448 22 .247 4 .503 1 .00 21 .49 N

ATOM 385 CA VAL A1032 -33 .692 21 .797 5 .868 1 .00 23 .88 C

ATOM 386 C VAL A1032 -33 .691 20 .275 5 .794 1 .00 24 .43 C

ATOM 387 O VAL A1032 -34 .377 19 .695 4 .950 1 .00 24 .91 O

ATOM 388 CB VAL A1032 -35 .045 22 .310 6 .403 1 .00 26 .33 C

ATOM 389 CGI VAL A1032 -35 .380 21 .674 7 .736 1 .00 24 .01 C

ATOM 390 CG2 VAL A1032 -34 .978 23 .794 6 .572 1 .00 28 .62 C

ATOM 391 N ASN A1033 -32 .909 19 .640 6 .664 1 .00 24 .42 N

ATOM 392 CA ASN A1033 -32 .811 18 .188 6 .694 1 .00 25 .74 C

ATOM 393 C ASN A1033 -34 .180 17 .579 6 .949 1 .00 26 .87 C

ATOM 394 O ASN A1033 -34 .963 18 .106 7 .741 1 .00 25 .76 O

ATOM 395 CB ASN A1033 -31 .849 17 .732 7 .795 1 .00 25 .60 C

ATOM 396 CG ASN A1033 -30 .411 18 .106 7 .509 1 .00 25 .10 C

ATOM 397 ODl ASN A1033 -30 .008 18 .249 6 .355 1, .00 26 .76 O

ATOM 398 ND2 ASN A1033 -29 .620 18 .255 8 .567 1 .00 28 .16 N

ATOM 399 N GLU A1034 -34 .464 16 .472 6 .271 1, .00 27 .31 N

ATOM 400 CA GLU A1034 -35, .738 15 .779 6 .443 1, .00 28 .71 C

ATOM 401 C GLU A1034 -35 .921 15 .415 7. .918 1, .00 27 .34 C

ATOM 402 O GLU A1034 -37 .043 15 .302 8 .407 1 .00 30 .30 O

ATOM 403 CB GLU A1034 -35, .775 14 .505 5 .586 1, .00 28, .07 c

ATOM 404 N SER A1035 -34 .799 15 .246 8 .614 1, .00 27 .97 N

ATOM 405 CA SER A1035 -34, .781 14 .885 10. .024 1, .00 26, .71 c

ATOM 406 C SER A1035 -34, .866 16 .063 10 .989 1, .00 26, .37 C

ATOM 407 O SER A1035 -34, .830 15 .867 12 .205 1, .00 27, .17 O

ATOM 408 CB SER A1035 -33, .517 14, .078 10, .329 1. .00 29, .54 C

ATOM 409 OG SER A1035 -32, .352 14 .797 9, .956 1. .00 34, .00 O

ATOM 410 N ALA A1036 -34, .973 17 .279 10, .456 1, .00 23, .09 N

ATOM 411 CA ALA A1036 -35. .055 18, .476 11, .293 1. .00 21. .09 C

ATOM 412 C ALA A1036 -36, .214 18, .380 12, .275 1. ,00 18, .43 C

ATOM 413 O ALA A1036 -37, .292 17, .917 11, .926 1, ,00 19, ,62 O

ATOM 414 CB ALA A1036 -35. .207 19, .716 10, .429 1. .00 20. .62 C

ATOM 415 N SER A1037 -35. .978 18, .813 13. .507 1. .00 19. .69 N

ATOM 416 CA SER A1037 -37. .006 18. ,791 14. .538 1. .00 19. .21 C

ATOM 417 C SER A1037 -37. .966 19, .969 14. .352 1. .00 18. .94 C

ATOM 418 O SER A1037 -37. .718 20, .868 13, .545 1. ,00 17. .04 O

ATOM 419 CB SER A1037 -36. .365 18. ,880 15. .919 1, ,00 20. ,11 C

ATOM 420 OG SER A1037 -35. .773 20. ,155 16. .092 1. .00 21. .38 O

ATOM 421 N LEU A1038 -39. .062 19, .955 15. ,101 1. .00 17. .70 N

ATOM 422 CA LEU A1038 -40. ,047 21. ,035 15. .047 1. .00 17. ,49 C

ATOM 423 C LEU A1038 -39. .400 22. ,360 15. .445 1. .00 17. ,70 c

ATOM 424 O LEU A1038 -39. ,629 23, .388 14, ,805 1. .00 16. .60 O

ATOM 425 CB LEU A1038 -41. ,209 20. .728 16. .003 1. ,00 19. ,41 c

ATOM 426 CG LEU A1038 -42. .296 21. .778 16. .189 1. .00 17. ,71 c

ATOM 427 CDl LEU A1038 -42. ,896 22, .140 14. ,827 1. ,00 18. ,08 c

ATOM 428 CD2 LEU A1038 -43. ,361 21, .228 17. .135 1. .00 18. ,16 c

ATOM 429 N ARG A1039 -38. .592 22, .329 16. .506 1. .00 18. ,12 N

ATOM 430 CA ARG A1039 -37. ,913 23. ,529 16. ,991 1. ,00 19. ,74 c

ATOM 431 C ARG A1039 -37. ,044 24. .126 15. .890 1. ,00 19. ,50 c

ATOM 432 O ARG A1039 -37. ,027 25, .341 15. .693 1. ,00 20. ,34 0

ATOM 433 CB ARG A1039 -37. ,055 23. ,205 18. .217 1. ,00 21. 08 c

ATOM 434 CG ARG A1039 -36. ,218 24. .384 18. ,697 1. 00 28. ,59 c

ATOM 435 CD ARG A1039 -35. ,182 23. ,957 19. .723 1. ,00 34. 11 c

< ? ATOM 436 NE ARG A1039 -35 . 548 24 . 354 21 .O79 1 . 00 41 . 03 N

ATOM 437 CZ ARG A1039 35 .547 23 .535 22 .129 1 .00 45 .31 C

ATOM 438 NHl ARG A1039 35 .207 22 .257 21 .989 1 .00 45 .83 N

ATOM 439 NH2 ARG A1039 35 .847 24 .005 23 .334 1 .00 47 .40 N

ATOM 440 N GLU A1040 36 .337 23 .261 15 .167 1 .00 17 .33 N

ATOM 441 CA GLU A1040 35 .465 23 .696 14 .083 1 .00 17 .94 C

ATOM 442 C GLU A1040 36 .240 24 .267 12 .901 1 .00 18 .49 C

ATOM 443 O GLU A1040 35 .805 25 .242 12 .285 1 .00 15 .50 O

ATOM 444 CB GLU A1040 34 .547 22 .550 13 .658 1 .00 18 .66 C

ATOM 445 CG GLU A1040 33 .584 22 .148 14 .777 1 .00 21 .90 C

ATOM 446 CD GLU A1040 32 .728 20 .936 14 .447 1 .00 24 .74 C

ATOM 447 OEl GLU A1040 33 .225 20 .003 13 .785 1 00 22 .23 O

ATOM 448 OE2 GLU A1040 31 .549 20 .918 14 .864 1 .00 28 .18 O

ATOM 449 N ARG A1041 37 .391 23 .668 12 .589 1 .00 18 .21 N

ATOM 450 CA ARG A1041 38 .229 24 .145 11 .492 1 .00 17 .26 C

ATOM 451 C ARG A1041 38 876 25 485 11 .852 1 00 17 .07 C

ATOM 452 O ARG A1041 39 .026 26 .357 10 .992 1 00 18 .01 O

ATOM 453 CB ARG A1041 39 .296 23 .104 11 .130 1 .00 20 .40 c

ATOM 454 CG ARG A1041 38 689 21 790 10 655 1 00 25 .20 c

ATOM 455 CD ARG A1041 39 716 20 793 10 .165 1 00 26 .55 c

ATOM 456 NE ARG A1041 39 063 19 534 9 812 1 00 31 .29 N

ATOM 457 CZ ARG A1041 38 562 19 249 8 611 1 00 30 66 C

ATOM 458 NHl ARG A1041 38 637 20 127 7 619 1 00 30 34 N

ATOM 459 NH2 ARG A1041 37 956 18 089 8 412 1 00 33 21 N

ATOM 460 N ILE A1042 39 255 25 648 13 .118 1 00 16 .70 N

ATOM 461 CA ILE A1042 39 854 26 901 13 580 1 00 20 02 C

ATOM 462 C ILE A1042 38 798 28 002 13 457 1 00 19 98 C

ATOM 463 O ILE A1042 39 092 29 115 13 013 1 00 20 91 O

ATOM 464 CB ILE A1042 40 356 26 794 15 059 1 00 21 84 C

ATOM 465 CGI ILE A1042 41 592 25 888 15 133 1 00 20 47 C

ATOM 466 CG2 ILE A1042 40 686 28 163 15 627 1 00 20 99 C

ATOM 467 CDl ILE A1042 42 099 25 634 16 546 1 00 20 08 C

ATOM 468 N GLU A1043 37 566 27 673 13 842 1 00 19 77 N

ATOM 469 CA GLU A1043 36 455 28 613 13 775 1 00 21 00 C

ATOM 470 C GLU A1043 36 168 29 047 12 340 1 00 20 02 c

ATOM 471 O GLU A1043 36 009 30 234 12 066 1 00 20 56 o

ATOM 472 CB GLU A1043 35 202 27 999 14 401 1 00 22 57 c

ATOM 473 CG GLU A1043 34 028 28 958 14 491 1 00 24 17 c

ATOM 474 CD GLU A1043 32 817 28 316 15 128 1 00 26 08 c

ATOM 475 OEl GLU A1043 32 824 28 117 16 361 1 00 29 76 0

ATOM 476 OE2 GLU A1043 31 864 27 996 14 395 1 00 26 82 o

ATOM 477 N PHE A1044 36 104 28 084 11 424 1 00 19 42 N

ATOM 478 CA PHE A1044 35 855 28 394 10 024 1 00 20 65 C

ATOM 479 C PHE A1044 36 969 29 269 9 444 1 00 20 47 c

ATOM 480 O PHE A1044 36 720 30 134 8 607 1 00 21 42 o

ATOM 481 CB PHE A1044 35 723 27 115 9 205 1 00 21 32 c

ATOM 482 CG PHE A1044 35 114 27 336 7 861 1 00 27 58 c

ATOM 483 CDl PHE A1044 33 952 28 091 7 735 1 00 31 08 c

ATOM 484 CD2 PHE A1044 35 696 26 804 6 721 1 00 29 77 c

ATOM 485 CEl PHE A1044 33 379 28 313 6 490 1 00 31 69 c

ATOM 486 CΞ2 PHE A1044 35 128 27 019 5 467 1 00 32 76 c

ATOM 487 CZ PHE A1044 33 966 27 776 5 356 1 00 31 21 c

ATOM 488 N LEU A1045 38 197 29 026 9 895 1 00 18 96 N

ATOM 489 CA LEU A1045 39 357 29 797 9 468 1 00 21 14 c

ATOM 490 C LEU A1045 39 161 31 277 9 824 1 00 19 32 c

ATOM 491 O LEU A1045 39 325 32 146 8 971 1 00 18 72 0

ATOM 492 CB LEU A1045 40 616 29 238 10 144 1 00 23 60 c

w ATOM 493 CG LEU A1045 -41.938 29.996 9.998 1.00 25.41 C

ATOM 494 CDl LEU A1045 -42 .237 30 .194 8 .536 1 .00 26 .40 C

ATOM 495 CD2 LEU A1045 -43 .062 29 .231 10 .675 1 .00 27 .56 C

ATOM 496 N ASN A1046 -38 .813 31 .550 11 .084 1 .00 21 .67 N

ATOM 497 CA ASN A1046 -38 .575 32 .919 11 .574 1, .00 23 .91 C

ATOM 498 C ASN A1046 -37 .432 33 .559 10 .801 1 .00 23 .29 C

ATOM 499 O ASN A1046 -37. .503 34 .718 10 .398 1 .00 23 .51 O

ATOM 500 CB ASN A1046 -38 .220 32 .908 13 .080 1 .00 25 .84 C

ATOM 501 CG ASN A1046 -37 .697 34 .273 13 .591 1 .00 25 .72 C

ATOM 502 ODl ASN A1046 -38 .470 35 .209 13 .809 1 .00 24 .46 O

ATOM 503 ND2 ASN A1046 -36 .382 34 .372 13 .800 1, .00 20 .34 N

ATOM 504 N GLU A1047 -36. .378 32 .779 10 .604 1 .00 23 .15 N

ATOM 505 CA GLU A1047 -35 .196 33 .227 9 .897 1 .00 22 .12 C

ATOM 506 C GLU A1047 -35 .513 33 .732 8 .491 1, .00 22 .27 C

ATOM 507 O GLU A1047 -35 .118 34 .836 8 .105 1 .00 22 .41 0

ATOM 508 CB GLU A1047 -34 .196 32 .074 9 .840 1, .00 23 .09 c

ATOM 509 CG GLU A1047 -32 .847 32 .459 9 .306 1 .00 26 .76 c

ATOM 510 CD GLU A1047 -31 .801 31 .374 9 .493 1, .00 24 .53 c

ATOM 511 OEl GLU A1047 -32, .033 30 .433 10 .282 1, .00 25 .08 o

ATOM 512 OE2 GLU A1047 -30, .740 31, .469 8, .850 1, .00 26 .93 O

ATOM 513 N ALA A1048 -36 .229 32 .919 7. .726 1, .00 18 .99 N

ATOM 514 CA ALA A1048 -36, .596 33, .282 6, .370 1, .00 18 .25 C

ATOM 515 C ALA A1048 -37, .575 34 .456 6 .376 1, ,00 17 .25 C

ATOM 516 O ALA A1048 -37, .503 35, .335 5, .519 1. .00 16 .43 O

ATOM 517 CB ALA A1048 -37, .205 32, .075 5 .657 1, .00 19 .42 C

ATOM 518 N SER A1049 -38 .481 34 .465 7 .351 1, .00 17 .19 N

ATOM 519 CA SER A1049 -39, .481 35, .527 7, .465 1. .00 19, .43 C

ATOM 520 C SER A1049 -38, .857 36 .902 7, .739 1, .00 19 .95 c

ATOM 521 O SER A1049 -39, .201 37, .884 7, .075 1. .00 20, .59 0

ATOM 522 CB SER A1049 -40, .504 35, .171 8, .547 1. .00 22 .44 c

ATOM 523 OG SER A1049 -41, .468 36, .194 8, .674 1. .00 27, .51 0

ATOM 524 N VAL A1050 -37, .944 36, .979 8, .708 1. .00 19 .57 N

ATOM 525 CA VAL A1050 -37. .294 38. .254 9. .014 1. .00 20, ,61 C

ATOM 526 C VAL A1050 -36. .429 38, .741 7, .844 1. .00 18, .53 C

ATOM 527 O VAL A1050 -36. .372 39. .939 7. .577 1. ,00 18. .80 O

ATOM 528 CB VAL A1050 -36. .444 38, .200 10. .311 1. ,00 20, ,35 C

ATOM 529 CGI VAL A1050 -37, .323 37. .907 11, .511 1. ,00 18, ,80 C

ATOM 530 CG2 VAL A1050 -35. ,351 37. .177 10, .187 1. ,00 23, .75 C

ATOM 531 N MET A1051 -35. .767 37, .820 7, .142 1. .00 19, ,12 N

ATOM 532 CA MET A1051 -34. .934 38. .196 5. .993 1. ,00 18. .67 C

ATOM 533 C MET A1051 -35. .750 38. .862 4, .896 1. .00 18, .59 c

ATOM 534 O MET A1051 -35. .272 39. .788 4. .240 1. ,00 20. .56 O

ATOM 535 CB MET A1051 -34. .217 36. .982 5. .393 1. ,00 19. .88 c

ATOM 536 CG MET A1051 -32. ,873 36. .662 6. .000 1. ,00 20. .60 c

ATOM 537 SD MET A1051 -32. .047 35. .284 5. .159 1. ,00 20. .60 s

ATOM 538 CE MET A1051 -31. .342 36. .097 3. .821 1. ,00 20. ,32 c

ATOM 539 N LYS A1052 -36. .978 38. .382 4. .693 1. ,00 18. ,22 N

ATOM 540 CA LYS A1052 -37. ,868 38. .933 3. ,673 1. ,00 18. .39 c

ATOM 541 C LYS A1052 -38. .093 40. .433 3. .852 1. .00 17. .75 c

ATOM 542 O LYS A1052 -38. .278 41. .154 2. .877 1. ,00 17. .08 0

ATOM 543 CB LYS A1052 -39. .229 38. .230 3. .709 1. ,00 18. .45 c

ATOM 544 CG LYS A1052 -39. .256 36. .861 3. .072 1. ,00 20. .53 c

ATOM 545 CD LYS A1052 -40. ,642 36. .253 3. .166 1. 00 22. .76 c

ATOM 546 CE LYS A1052 -40. .696 34. .887 2. .499 1. ,00 25. .86 c

ATOM 547 NZ LYS A1052 -42. ,054 34. .291 2. ,667 1. 00 29. ,77 N

ATOM 548 N GLY A1053 -38. .074 40. .892 5. .100 1. ,00 17. .25 N

ATOM 549 CA GLY A1053 -38. ,308 42. ,299 5. ,370 1. 00 17. ,62 C

ψ - ATOM 550 C GLY A1053 -37.107 43.223 5.306 1.00 19.01 C

ATOM 551 O GLY A1053 -37 .261 44 .439 5 .427 1 .00 19 .14 O

ATOM 552 N PHE A1054 -35 .923 42 .667 5 .071 1 .00 17 .34 N

ATOM 553 CA PHE A1054 -34 .698 43 .466 5 .034 1 .00 17 .69 C

ATOM 554 C PHE A1054 -34 .192 43 .819 3 .647 1 .00 17 .60 C

ATOM 555 O PHE A1054 -34 .241 43 .000 2 .730 1 .00 16 .97 O

ATOM 556 CB PHE A1054 -33 .570 42 .736 5 .785 1 .00 17 .37 C

ATOM 557 CG PHE A1054 -33 .852 42 .494 7 .245 1 .00 19 .31 c

ATOM 558 CDl PHE A1054 -34 .750 43 .298 7 .947 1 .00 19 .12 c

ATOM 559 CD2 PHE A1054 -33 .219 41 .451 7 .920 1 .00 17 .42 c

ATOM 560 CE1 PHE A1054 -35 .014 43 .067 9 .299 1 .00 20 .65 c

ATOM 561 CΞ2 PHE A1054 -33 .476 41 .211 9 .274 1 .00 20 .14 c

ATOM 562 CZ PHE A1054 -34 .376 42 .021 9 .965 1 .00 22 .51 c

ATOM 563 N THR A1055 -33 .704 45 .052 3 .514 1 .00 17 .36 N

ATOM 564 CA THR A1055 -33 .113 45 .556 2 .279 1 .00 17 .45 C

ATOM 565 C THR A1055 -31 .949 46 .459 2 .680 1 .00 16 .53 C

ATOM 566 O THR A1055 -32 .114 47 .661 2 .908 1 .00 16 .20 0

ATOM 567 CB THR A1055 -34 .108 46 .336 1 .401 1 .00 18 .73 c

ATOM 568 OG1 THR A1055 -35 .139 45 .450 0 .957 1 .00 21 .30 0

ATOM 569 CG2 THR A1055 -33 .400 46 .902 0 .175 1 .00 20 .27 c

ATOM 570 N CYS A1056 -30 .770 45 .853 2 .776 1 .00 15 .54 N

ATOM 571 CA CYS A1056 -29 .557 46 .566 3 .160 1 .00 13 .50 C

ATOM 572 C CYS A1056 -28 .364 45 .906 2 .495 1 .00 11 .53 c

ATOM 573 O CYS A1056 -28 .264 44 .681 2 .460 1, ,00 11, .99 0

ATOM 574 CB CYS A1056 -29 .373 46 .544 4 .685 1, .00 13, .69 c

ATOM 575 SG CYS A1056 -27, .890 47 .434 5 .305 1 .00 11, .29 s

ATOM 576 N HIS A1057 -27 .461 46 .722 1 .980 1, .00 9, .93 N

ATOM 577 CA HIS A1057 -26, .273 46. .222 1. .307 1, .00 12. .65 C

ATOM 578 C HIS A1057 -25, .400 45 .394 2. .251 1, .00 12. ,19 c

ATOM 579 O HIS A1057 -24, .645 44 .532 1 .806 1, .00 12, .30 0

ATOM 580 CB HIS A1057 -25, .463 47 .397 0 .757 1, .00 10. .35 c

ATOM 581 CG HIS A1057 -24. .288 46, .989 -0, .070 1. ,00 12. ,99 c

ATOM 582 ND1 HIS A1057 -24. .409 46, .586 -1, .383 1. ,00 13. ,24 N

ATOM 583 CD2 HIS A1057 -22. .966 46, .921 0, .225 1. .00 10. .68 C

ATOM 5,84 CΞ1 HIS A1057 -23. .212 46, ,290 -1, .863 1. ,00 15. .50 C

ATOM 585 NE2 HIS A1057 -22. .321 46. .483 -0. .907 1. ,00 8. ,94 N

ATOM 586 N HIS A1058 -25. .505 45. .659 3. .551 1. ,00 11. ,39 N

ATOM 587 CA HIS A1058 -24. .687 44. .952 4. .534 1. ,00 10. .26 C

ATOM 588 C HIS A1058 -25. .410 43. .878 5. .327 1. ,00 8. .83 C

ATOM 589 O HIS A1058 -25. ,001 43. ,513 6. ,435 1. 00 9. ,69 O

ATOM 590 CB HIS A1058 -23. ,991 45. .962 5. .450 1. ,00 9. ,91 C

ATOM 591 CG HIS A1058 -23. ,078 46. .892 4. .712 1. ,00 12. ,57 C

ATOM 592 ND1 HIS A1058 -23. ,243 48. .258 4. .705 1. 00 10. .25 N

ATOM 593 CD2 HIS A1058 -22. ,015 46. .642 3. ,903 1. 00 12. 55 C

ATOM 594 CE1 HIS A1058 -22. ,333 48. .813 3. ,925 1. 00 10. 94 C

ATOM 595 NE2 HIS A1058 -21. ,577 47. .848 3. ,427 1. 00 12. 86 N

ATOM 596 N VAL A1059 -26. ,485 43. .366 4. ,742 1. 00 8. 67 N

ATOM 597 CA VAL A1059 -27. 282 42. ,307 5. 348 1. 00 8. 36 C

ATOM 598 C VAL A1059 -27. 530 41. ,341 4. ,202 1. 00 10. 14 C

ATOM 599 O VAL A1059 -27. 933 41. ,765 3. ,114 1. 00 10. 68 O

ATOM 600 CB VAL A1059 -28. 640 42. ,850 5. ,865 1. 00 11. 02 C

ATOM 601 CGI VAL A1059 -29. 503 41. ,705 6. 407 1. 00 10. 80 C

ATOM 602 CG2 VAL A1059 -28. 406 43. ,884 6. 969 1. 00 13. 92 C

ATOM 603 N VAL A1060 -27. 287 40. ,052 4. 440 1. 00 10. 95 N

ATOM 604 CA VAL A1060 -27. 480 39. ,033 3. 409 1. 00 11. 47 C

ATOM 605 C VAL A1060 -28. 929 39. 027 2. 912 1. 00 10. 83 C

ATOM 606 O VAL A1060 -29. 870 38. 904 3. 688 1. 00 11. 05 O

φ ATOM 607 CB VAL A1060 -27.056 37.620 3.903 1.00 11.60 C

ATOM 608 CGI VAL A1060 -27 .314 36 .584 2 .815 1 .00 10 .07 C

ATOM 609 CG2 VAL A1060 -25 .557 37 .623 4 .281 1 .00 11 .71 C

ATOM 610 N ARG A1061 -29 .059 39 .153 1 .597 1 .00 11 .98 N

ATOM 611 CA ARG A1061 -30 .327 39 .227 0 .891 1 .00 14 .94 C

ATOM 612 C ARG A1061 -30 .950 37 .882 0 .558 1 .00 15 .18 C

ATOM 613 O ARG A1061 -30 .267 36 .963 0 .108 1 .00 13 .79 0

ATOM 614 CB ARG A1061 -30 .102 40 .015 -0 .398 1 .00 15 .31 c

ATOM 615 CG ARG A1061 -31 .329 40 .291 -1 .252 1 .00 22 .12 c

ATOM 616 CD ARG A1061 -30 .917 41 .039 -2 .516 1 .00 25 .51 c

ATOM 617 NE ARG A1061 -32 .042 41 .258 -3 .425 1 .00 31 .31 N

ATOM 618 CZ ARG A1061 -31 .926 41 .676 -4 .686 1 .00 31 .86 C

ATOM 619 NHl ARG A1061 -30 .733 41 .935 -5 .207 1 .00 31 .52 N

ATOM 620 NH2 ARG A1061 -33 .008 41 .816 -5 .439 1 .00 29, .64 N

ATOM 621 N LEU A1062 -32 .255 37 .781 0 .801 1 .00 15 .94 N

ATOM 622 CA LEU A1062 -33 .022 36 .587 0 .468 1 .00 16. .43 C

ATOM 623 C LEU A1062 -33 .531 36 .881 -0 .941 1 .00 16, .38 C

ATOM 624 O LEU A1062 -34 .010 37, .980 -1 .216 1, .00 19, .01 O

ATOM 625 CB LEU A1062 -34 .209 36 .404 1 .417 1 .00 18 .45 C

ATOM 626 CG ^■LEU A1062 -35 .169 35 .282 0 .988 1 .00 22 .97 C

ATOM 627 CDl LEU A1062 -34 .552 33, .944 1 .324 1 .00 25 .57 C

ATOM 628 CD2 LEU A1062 -36 .517 35 .418 1 .661 1 .00 26 .56 C

ATOM 629 N LEU A1063 -33, .422 35, .905 -1 .831 1, .00 14, .79 N

ATOM 630 CA LEU A1063 -33 .847 36, .068 -3 .213 1, .00 14, .15 C

ATOM 631 C LEU A1063 -35 .116 35 .301 -3 .580 1, .00 17, .00 C

ATOM 632 O LEU A1063 -35, .820 35, .670 -4 .523 1, .00 19, ,40 O

ATOM 633 CB LEU A1063 -32 .713 35 .658 -4 .155 1, .00 13, .74 C

ATOM 634 CG LEU A1063 -31, .420 36, .468 -4 .067 1, .00 13, .25 C

ATOM 635 CDl LEU A1063 -30, .387 35, .859 -5 .005 1, .00 12, .67 C

ATOM 636 CD2 LEU A1063 -31 .697 37 .910 -4 .452 1, .00 14, .12 C

ATOM 637 N GLY A1064 -35, .416 34, .235 -2 .849 1, .00 15. ,45 N

ATOM 638 CA GLY A1064 -36, .614 33, .477 -3 .158 1, .00 14, ,47 C

ATOM 639 C GLY A1064 -36, .731 32, .213 -2, .351 1. .00 14. .35 C

ATOM 640 O GLY A1064 -35, .813 31, .852 -1 .611 1. .00 12. .52 O

ATOM 641 N VAL A1065 -37, .882 31. .558 -2, .459 1. .00 15. .85 N

ATOM 642 CA VAL A1065 -38, .125 30. .326 -1, .729 1. .00 17. .73 C

ATOM 643 C VAL A1065 -38, .826 29, .335 -2 .638 1, .00 18. .46 C

ATOM 644 O VAL A1065 -39, .816 29. .660 -3, .289 1. .00 20. .10 O

ATOM 645 CB VAL A1065 -39, ,028 30, .547 -0, .485 1. .00 20. .16 C

ATOM 646 CGI VAL A1065 -39. .204 29. .243 0, .274 1. .00 23. .93 C

ATOM 647 CG2 VAL A1065 -38, .439 31. .615 0, .442 1. .00 20. .86 C

ATOM 648 N VAL A1066 -38, .293 28, ,124 -2, .694 1. .00 19. .65 N

ATOM 649 CA VAL A1066 -38. .899 27. .072 -3, .490 1. .00 21. ,89 C

ATOM 650 C VAL A1066 -39, ,637 26. .204 -2, .483 1. .00 25. .97 C

ATOM 651 O VAL A1066 -39. .020 25. .509 -1, .673 1. ,00 23. ,58 O

ATOM 652 CB VAL A1066 -37. .854 26. .226 -4, .235 1. .00 19. ,41 C

ATOM 653 CGI VAL A1066 -38. .551 25. .133 -5, .039 1. .00 21. .62 C

ATOM 654 CG2 VAL A1066 -37. .023 27. .097 -5, .158 1. ,00 19. ,23 C

ATOM 655 N SER A1067 -40, .963 26. .266 -2, .519 1. .00 31. .27 N

ATOM 656 CA SER A1067 -41. .773 25. ,475 -1. .606 1. ,00 36. ,55 C

ATOM 657 C SER A1067 -42, .712 24. .540 -2, ,348 1. ,00 39. .09 C

ATOM 658 O SER A1067 -43. .436 23. .760 -1. ,733 1. ,00 40. ,90 O

ATOM 659 CB SER A1067 -42. .547 26. .376 -0. .652 1. ,00 38. ,00 C

ATOM 660 OG SER A1067 -43, .264 27. .376 -1, ,352 1. .00 40. .12 O

ATOM 661 N LYS A1068 -42. .698 24. .628 -3. ,671 1. ,00 41. ,03 N

ATOM 662 CA LYS A1068 -43, .523 23. ,767 -4, .500 1. ,00 42. ,50 C

ATOM 663 C LYS A1068 -42. .832 22. ,405 -4. .551 1. ,00 43. ,63 C

M ATOM 664 O LYS A1068 -42.134 22.076 -5.518 1.00 44.79 O

ATOM 665 CB LYS A1068 -43 .670 24 .354 -5 .906 1 .00 42 .61 C

ATOM 666 N GLY A1069 -43 .026 21 .630 -3 .488 1 .00 43 .36 N

ATOM 667 CA GLY A1069 -42 .430 20 .312 -3 .394 1 .00 41 .96 C

ATOM 668 C GLY A1069 -41 .399 20 .213 -2 .288 1 .00 41 .59 C

ATOM 669 O GLY A1069 -41 .253 21 .125 -1 .467 1 .00 41 .15 O

ATOM 670 N GLN A1070 -40 .678 19 .097 -2 .273 1 .00 40 .63 N

ATOM 671 CA GLN A1070 -39 .646 18 .855 -1 .274 1 .00 39 .88 C

ATOM 672 C GLN A1070 -38 .301 18 .557 -1 .946 1 .00 37 .54 C

ATOM 673 O GLN A1070 -38 .258 18 .049 -3 .072 1 .00 38 .58 O

ATOM 674 CB GLN A1070 -40 .053 17 .689 -0 .362 1 .00 40 .63 C

ATOM 675 N PRO A1071 -37 .192 18 .991 -1 .318 1 .00 33 .49 N

ATOM 676 CA PRO A1071 -37 .179 19 .729 -0 .050 1 .00 29 .97 C

ATOM 677 C PRO A1071 -37 .344 21 .238 -0 .275 1 .00 27 .03 C

ATOM 678 O PRO A1071 -37 .110 21 .738 -1 .376 1 .00 25 .49 O

ATOM 679 CB PRO A1071 -35 .795 19 .408 0 .501 1 .00 31 .03 C

ATOM 680 CG PRO A1071 -34 .964 19 .376 -0 .737 1 .00 30 .62 C

ATOM 681 CD PRO A1071 -35 .824 18 .590 -1 .701 1 .00 33 .16 C

ATOM 682 N THR A1072 -37 .750 21 .956 0 .769 1 .00 26 .23 N

ATOM 683 CA THR A1072 -37 .917 23 .410 0 .680 1 .00 25 .77 C

ATOM 684 C THR A1072 -36 .524 24 .008 0 .481 1 .00 22 .95 C

ATOM 685 O THR A1072 -35 .580 23 .599 1 .153 1 .00 24 .11 O

ATOM 686 CB THR A1072 -38 .515 23 .998 1 .986 1. .00 27 .65 C

ATOM 687 OG1 THR A1072 -39 .793 23 .403 2 .245 1 .00 31 .53 O

ATOM 688 CG2 THR A1072 -38, .682 25 .519 1 .875 1, .00 27 .39 C

ATOM 689 N LEU A1073 -36, .396 24 .958 -0 .441 1, .00 22, .21 N

ATOM 690 CA LEU A1073 -35, .107 25 .600 -0 .703 1, .00 19, .29 C

ATOM 691 C LEU A1073 -35 .204 27 .094 -0 .447 1 .00 17 .69 C

ATOM 692 O LEU A1073 -36, .107 27, .750 -0 .960 1. .00 18, .36 0

ATOM 693 CB LEU A1073 -34, .687 25, .402 -2 .167 1, .00 20, .43 C

ATOM 694 CG LEU A1073 -34, .690 24, .021 -2 .829 1, ,00 19, .65 C

ATOM 695 CDl LEU A1073 -34, .282 24, .162 -4 .283 1, .00 21, .71 C

ATOM 696 CD2 LEU A1073 -33. .759 23, ,066 -2, .095 1. .00 21, .12 c

ATOM 697 N VAL A1074 -34. .286 27, .634 0, .345 1, .00 15, ,25 N

ATOM 698 CA VAL A1074 -34, .265 29, .074 0, .596 1, .00 15, .88 C

ATOM 699 C VAL A1074 -33. .082 29. .618 -0. .204 1. .00 15. .47 C

ATOM 700 O VAL A1074 -31. .923 29. .291 0, .071 1. .00 13. .19 O

ATOM 701 CB VAL A1074 -34. .148 29. .404 2, .095 1. .00 17. .14 C

ATOM 702 CGI VAL A1074 -33. .778 30. ,873 2, ,291 1. .00 16. .99 C

ATOM 703 CG2 VAL A1074 -35. ,483 29, .116 2, .776 1. .00 17. .81 C

ATOM 704 N VAL A1075 -33. ,394 30. .438 -1. .202 1. ,00 12. ,90 N

ATOM 705 CA VAL A1075 -32. .393 31. .002 -2. ,093 1. ,00 11. .29 C

ATOM 706 C VAL A1075 -31. ,957 32. .375 -1. ,606 1. ,00 13. .33 C

ATOM 707 O VAL A1075 -32. ,781 33. .267 -1. .446 1. ,00 11. ,74 O

ATOM 708 CB VAL A1075 -32. ,941 31. .060 -3. .555 1. ,00 9. ,65 C

ATOM 709 CGI VAL A1075 -31. .846 31. ,453 -4. .528 1. ,00 10. ,47 C

ATOM 710 CG2 VAL A1075 -33. ,541 29. ,704 -3. ,942 1. 00 10. ,25 C

ATOM 711 N MET A1076 -30. ,652 32. ,529 -1. ,381 1. ,00 11. ,81 N

ATOM 712 CA MET A1076 -30. ,066 33. .782 -0. .882 1. ,00 13. ,16 C

ATOM 713 C MET A1076 -28. ,950 34. ,270 -1. .797 1. ,00 12. ,22 C

ATOM 714 O MET A1076 -28. ,521 33. ,549 -2. ,700 1. 00 12. 11 0

ATOM 715 CB MET A1076 -29. ,456 33. ,533 0. ,502 1. ,00 13. ,48 c

ATOM 716 CG MET A1076 -30. ,440 33. ,074 1. ,571 1. ,00 20. ,12 c

ATOM 717 SD MET A1076 -29. 599 32. 223 2. 938 1. 00 26. 55 s

ATOM 718 CE MET A1076 -28. ,517 33. ,445 3. ,471 1. 00 27. ,81 c

ATOM 719 N GLU A1077 -28. ,465 35. ,492 -1. ,571 1. 00 10. 13 N

ATOM 720 CA GLU A1077 -27. ,361 35. ,991 -2. ,385 1. 00 13. ,26 c

¥& ATOM 721 C GLU A1077 -26.131 35.164 -1.996 1.00 11.84 C

ATOM 722 O GLU A1077 -25 .978 34 .769 -0 .837 1 .00 14 .12 O

ATOM 723 CB GLU A1077 -27 .111 37 .492 -2 .150 1 .00 15 .64 C

ATOM 724 CG GLU A1077 -26 .193 37 .829 -0 .993 1 .00 14 .98 C

ATOM 725 CD GLU A1077 -26 .043 39 .328 -0 .797 1 .00 12 .66 C

ATOM 726 OEl GLU A1077 -25 .222 39 .957 -1 .487 1 .00 13 .76 O

ATOM 727 OΞ2 GLU A1077 -26 .746 39 .879 0 .064 1 .00 15 .99 O

ATOM 728 N LEU A1078 -25 .274 34 .885 -2 .964 1 .00 13 .35 N

ATOM 729 CA LEU A1078 -24 .074 34 .113 -2 .677 1 .00 13 .13 C

ATOM 730 C LEU A1078 -23 .012 34 .999 -2 .060 1 .00 13 .33 C

ATOM 731 O LEU A1078 -22 .738 36 .090 -2 .563 1 .00 13 .52 O

ATOM 732 CB LEU A1078 -23 .495 33 .500 -3 .951 1 .00 11 .18 C

ATOM 733 CG LEU A1078 -22 .173 32 .730 -3 .804 1 .00 9 .29 C

ATOM 734 CDl LEU A1078 -22 .387 31 .453 -3 .014 1 .00 11 .89 c

ATOM 735 CD2 LEU A1078 -21 .613 32 .406 -5 .172 1 .00 12 .79 c

ATOM 736 N MET A1079 -22 .430 34 .519 -0 .967 1 .00 13 .38 N

ATOM 737 CA MET A1079 -21 .335 35 .207 -0 .285 1 .00 14, .14 c

ATOM 738 C MET A1079 -20 .193 34 .218 -0 .559 1 .00 13 .72 C

ATOM 739 O MET A1079 -19 .946 33, .310 0 .225 1 .00 13 .63 O

ATOM 740 CB MET A1079 -21 .631 35 .333 1 .208 1 .00 11 .60 C

ATOM 741 CG MET A1079 -22 .892 36 .155 1 .505 1 .00 13 .51 C

ATOM 742 SD MET A1079 -22 .808 37, .834 0 .828 1 .00 14 .09 S

ATOM 743 CE MET A1079 -21 .776 38 .589 2 .055 1 .00 13 .54 C

ATOM 744 N ALA A1080 -19 .531 34 .410 -1 .698 1 .00 15, .88 N

ATOM 745 CA ALA A1080 -18, .457 33, .541 -2 .193 1, ,00 16, .20 C

ATOM 746 C ALA A1080 -17 .391 33, .071 -1 .209 1, .00 18, .77 C

ATOM 747 O ALA A1080 -16 .936 31 .917 -1 .281 1, .00 18, .09 O

ATOM 748 CB ALA A1080 -17, .801 34, .168 -3 .416 1, .00 15, .71 C

ATOM 749 N HIS A1081 -16, .988 33, .951 -0 .299 1, .00 16, .70 N

ATOM 750 CA HIS A1081 -15, ,963 33, .596 0, .681 1, .00 16. .63 C

ATOM 751 C HIS A1081 -16, .474 33, .015 1 .993 1, .00 16, ,49 c

ATOM 752 O HIS A1081 -15, .727 32, .930 2 .965 1, .00 18, .85 O

ATOM 753 CB HIS A1081 -15, .038 34, .781 0, ,929 1. ,00 16. .13 c

ATOM 754 CG HIS A1081 -14, .202 35. .121 -0, .254 1. .00 18. .59 c

ATOM 755 NDl HIS A1081 -13, .228 34, .274 -0 .740 1, .00 22. .21 N

ATOM 756 CD2 HIS A1081 -14, .224 36. .189 -1, .086 1. .00 19. .31 c

ATOM 757 CΞl HIS A1081 -12, .685 34, .807 -1, .820 1. ,00 21. .67 c

ATOM 758 NE2 HIS A1081 -13. .272 35. ,969 -2, ,049 1, .00 21. ,13 N

ATOM 759 N GLY A1082 -17. ,743 32. .617 2, .008 1. .00 14. ,45 N

ATOM 760 CA GLY A1082 -18, .339 32, .011 3, ,186 1, .00 13. ,25 C

ATOM 761 C GLY A1082 -18. .413 32. .884 4. .425 1. .00 12. .24 C

ATOM 762 O GLY A1082 -18. .442 34. .110 4, .332 1. .00 14. .02 O

ATOM 763 N ASP A1083 -18, .463 32. .238 5, .585 1, .00 10. .74 N

ATOM 764 CA ASP A1083 -18. .563 32. .939 6. .857 1. .00 11. ,68 C

ATOM 765 C ASP A1083 -17. .236 33. .543 7, ,279 1. ,00 12. .40 C

ATOM 766 O ASP A1083 -16. .171 33. .007 6, .967 1, .00 10. .71 O

ATOM 767 CB ASP A1083 -19. .070 31. .989 7. ,934 1. ,00 11. .72 C

ATOM 768 CG ASP A1083 -18. ,097 30. .879 8. .221 1. .00 14. .75 C

ATOM 769 ODl ASP A1083 -17. ,991 29. ,946 7. .402 1. ,00 14. ,32 O

ATOM 770 OD2 ASP A1083 -17. .418 30. ,956 9. .255 1. .00 14. .30 O

ATOM 771 N LEU A1084 -17. .311 34. .654 8. .005 1. ,00 12. .89 N

ATOM 772 CA LEU A1084 -16. .121 35. .370 8. ,456 1. ,00 13. ,20 C

ATOM 773 C LEU A1084 -15. .157 34. .551 9. .311 1. .00 12. ,93 C

ATOM 774 O LEU A1084 -13. .947 34. .720 9. ,185 1. .00 12. .58 O

ATOM 775 CB LEU A1084 -16. ,520 36. ,657 9. ,186 1. ,00 12. ,11 C

ATOM 776 CG LEU A1084 -15. ,419 37. .647 9. .598 1. .00 13. ,13 c

ATOM 777 CDl LEU A1084 -14. .583 38. .104 8. .397 1, .00 11. .10 c ATOM 778 CD2 LEU A1084 -16.075 38.833 10.275 1.00 11.47 C

ATOM 779 N LYS A1085 -15 .677 33 .669 10 .169 1 .00 12 .56 N

ATOM 780 CA LYS A1085 -14 .801 32 .864 11 .011 1 .00 12 .94 C

ATOM 781 C LYS A1085 -13 .875 31 .994 10 .158 1 .00 14 .74 C

ATOM 782 O LYS A1085 -12 .660 32 .016 10 .346 1. .00 15 .74 O

ATOM 783 CB LYS A1085 -15 .600 31 .991 11 .990 1 .00 13 .32 C

ATOM 784 CG LYS A1085 -14 .701 31 .111 12 .842 1 .00 14 .28 C

ATOM 785 CD LYS A1085 -15 .442 30 .395 13 .949 1 .00 12 .36 C

ATOM 786 CE LYS A1085 -14 .539 29 .341 14 .565 1 .00 16 .49 C

ATOM 787 NZ LYS A1085 -15, .242 28 .496 15 .586 1, .00 13 .78 N

ATOM 788 N SER A1086 -14 .464 31 .242 9 .227 1, .00 14 .33 N

ATOM 789 CA SER A1086 -13. .724 30 .374 8 .308 1 .00 16 .22 C

ATOM 790 C SER A1086 -12 .728 31 .197 7 .497 1, .00 15 .84 C

ATOM 791 O SER A1086 -11 .559 30 .834 7 .363 1, .00 15 .53 O

ATOM 792 CB SER A1086 -14 .697 29 .695 7 .329 1, .00 18 .16 C

ATOM 793 OG SER A1086 -15 .494 28 .729 7 .984 1 .00 22 .67 O

ATOM 794 N TYR A1087 -13, .214 32 .307 6 .951 1, .00 14 .09 N

ATOM 795 CA TYR A1087 -12 .393 33 .197 6 .152 1 .00 14 .29 C

ATOM 796 C TYR A1087 -11, .143 33 .675 6 .910 1, .00 12 .31 C

ATOM 797 O TYR A1087 -10 .029 33 .603 6 .390 1, .00 12 .67 O

ATOM 798 CB TYR A1087 -13, .227 34 .400 5 .695 1, .00 13 .02 C

ATOM 799 CG TYR A1087 -12 .448 35 .367 4. .847 1, .00 13 .05 C

ATOM 800 CDl TYR A1087 -11, .963 34, .985 3 .601 1, .00 15 .15 C

ATOM 801 CD2 TYR A1087 -12 .155 36 .658 5. .307 1, ,00 13 .31 C

ATOM 802 CE1 TYR A1087 -11, .199 35, .854 2, .829 1, ,00 16 .79 C

ATOM 803 CE2 TYR A1087 -11, .388 37 .536 4 .539 1, .00 17 .77 C

ATOM 804 CZ TYR A1087 -10, .915 37, .122 3, .303 1, .00 17 .99 C

ATOM 805 OH TYR A1087 -10, .142 37 .961 2 .536 1, .00 24 .42 O

ATOM 806 N LEU A1088 ^' -11, .340 34, .156 8, .135 1. .00 10, .80 N

ATOM 807 CA LEU A1088 -10, .246 34 .652 8 .973 1. .00 13 .33 C

ATOM 808 C LEU A1088 -9, .207 33, .567 9, .233 1. ,00 13 .98 C

ATOM 809 O LEU A1088 -7 .997 33, .807 9, .126 1. .00 13 .52 O

ATOM 810 CB LEU A1088 -10, .787 35, .174 10, .307 1. ,00 7, .67 C

ATOM 811 CG LEU A1088 -11, .551 36, .502 10, .244 1. .00 11 .49 C

ATOM 812 CDl LEU A1088 -12, .284 36, .741 11, .557 1. ,00 6, .85 C

ATOM 813 CD2 LEU A1088 -10, .606 37, .654 9, .923 1. ,00 9 .68 C

ATOM 814 N ARG A1089 -9, .683 32. .374 9, .572 1. ,00 14, .52 N

ATOM 815 CA ARG A1089 -8, .780 31, .263 9, .837 1. ,00 16 .81 C

ATOM 816 C ARG A1089 -7, .958 30, .900 8, .611 1. ,00 16, .25 C

ATOM 817 O ARG A1089 -6, .789 30, ,518 8, ,734 1. .00 15 .74 O

ATOM 818 CB ARG A1089 -9, .541 30, .056 10 .392 1. ,00 17 .36 C

ATOM 819 CG ARG A1089 -10. .027 30, .287 11, .811 1. ,00 18, .52 C

ATOM 820 CD ARG A1089 -10, .628 29, .050 12, .452 1. ,00 23 .37 C

ATOM 821 NE ARG A1089 -10. .936 29, .302 13, .861 1. ,00 26, ,25 N

ATOM 822 CZ ARG A1089 -11, .213 28, .361 14, .761 1. .00 27, .51 C

ATOM 823 NHl ARG A1089 -11. .233 27, .078 14, .412 1. ,00 28, ,13 N

ATOM 824 NH2 ARG A1089 -11, .443 28, .703 16, .024 1. ,00 24, .13 N

ATOM 825 N SER A1090 -8, .549 31, .046 7, .430 1. ,00 15, .96 N

ATOM 826 CA SER A1090 -7, .834 30, .732 6, .200 1. .00 16 .38 C

ATOM 827 C SER A1090 -6, .708 31. .731 5, .936 1. ,00 17, .14 C

ATOM 828 O SER A1090 -5, .789 31, .453 5, .166 1. ,00 18 .21 O

ATOM 829 CB SER A1090 -8, .789 30. .688 5. .003 1. 00 16, .56 C

ATOM 830 OG SER A1090 -9, .068 31, .979 4, .493 1. ,00 16, .84 O

ATOM 831 N LEU A1091 -6. .780 32, .889 6, .586 1. ,00 17, .32 N

ATOM 832 CA LEU A1091 -5, .777 33, .932 6, ,415 1. ,00 18. .17 C

ATOM 833 C LEU A1091 -4. .599 33. .812 7. ,372 1. ,00 19, .26 C

ATOM 834 O LEU A1091 -3, ,691 34, .647 7, .362 1. ,00 18, .90 O ATOM 835 CB LEU A1091 -6.416 35.319 6.509 1.00 14.92 C

ATOM 836 CG LEU A1091 -7 .405 35 .654 5 .391 1 .00 15 .35 C

ATOM 837 CDl LEU A1091 -7 .993 37 .044 5 .632 1 .00 17 .36 C

ATOM 838 CD2 LEU A1091 -6 .711 35 .592 4 .034 1 .00 16 .54 C

ATOM 839 N ARG A1092 -4 .619 32 .782 8 .213 1 .00 19 .97 N

ATOM 840 CA ARG A1092 -3 .509 32 .540 9 .119 1 .00 22 .42 C

ATOM 841 C ARG A1092 -2 .385 32 .101 8 .174 1 .00 25 .89 C

ATOM 842 O ARG A1092 -2 .611 31 .285 7 .279 1 .00 25 .84 O

ATOM 843 CB ARG A1092 -3 .871 31 .441 10 .117 1, .00 21 .95 C

ATOM 844 CG ARG A1092 -4 .972 31 .840 11 .091 1, .00 20 .81 C

ATOM 845 CD ARG A1092 -5 .227 30 .750 12 .108 1, .00 25 .43 C

ATOM 846 NE ARG A1092 -6 .287 31 .107 13 .051 1, .00 26 .60 N

ATOM 847 CZ ARG A1092 -6 .741 30 .303 14 .008 1 .00 27 .98 C

ATOM 848 NHl ARG A1092 -6 .229 29 .086 14 .164 1, .00 27 .80 N

ATOM 849 NH2 ARG A1092 -7 .737 30 .699 14 .786 1 .00 24 .55 N

ATOM 850 N PRO A1093 -1 .184 32 .689 8 .311 1 .00 28 .15 N

ATOM 851 CA PRO A1093 -0 .047 32 .347 7 .446 1, .00 30 .22 C

ATOM 852 C PRO A1093 0 .222 30 .858 7 .226 1, .00 30 .73 C

ATOM 853 O PRO A1093 0 .597 30 .454 6 .123 1, .00 31 .65 O

ATOM 854 CB PRO A1093 1 .132 33 .069 8 .118 1, ,00 29 .99 C

ATOM 855 CG PRO A1093 0 .703 33 .199 9 .546 1, .00 32 .89 C

ATOM 856 CD PRO A1093 -0 .751 33 .582 9 .399 1, .00 31 .11 C

ATOM 857 N GLU A1094 0 .021 30 .049 8 .261 1, .00 29 .81 N

ATOM 858 CA GLU A1094 0 .253 28 .613 8. .167 1. .00 31 .45 C

ATOM 859 C GLU A1094 -0 .981 27 .794 7. .785 1, .00 33 .19 c

ATOM 860 O GLU A1094 -0 .966 26 .568 7 .890 1, ,00 34 .69 O

ATOM 861 CB GLU A1094 0 .826 28 .089 9 .489 1, ,00 33 .28 c

ATOM 862 N ALA A1095 -2 .044 28, .465 7, .344 1. .00 32 .55 N

ATOM 863 CA ALA A1095 -3 .284 27, .787 6, .958 1. .00 31, .68 c

ATOM 864 C ALA A1095 -3 .118 26, .934 5, .703 1. .00 30, .77 C

ATOM 865 O ALA A1095 -2 .552 27, .383 4, .702 1. .00 30, .92 O

ATOM 866 CB ALA A1095 -4, .408 28, .807 6, .756 1. .00 26, .81 C

ATOM 867 N GLU A1096 -3, .619 25, ,702 5, .766 1. .00 30. .97 N

ATOM 868 CA GLU A1096 -3, .543 24, .780 4, .637 1. .00 31, .22 C

ATOM 869 C GLU A1096 -4, .333 25, .323 3, .451 1. .00 31, .81 C

ATOM 870 O GLU A1096 -3, .988 25. .082 2. .291 1. ,00 32. .78 O

ATOM 871 CB GLU A1096 -4, .083 23. .404 5, .036 1. ,00 30, .63 c

ATOM 872 N ASN A1097 -5, ,396 26. .063 3, .758 1. ,00 30. .85 N

ATOM 873 CA ASN A1097 -6, ,245 26. .656 2, .737 1. ,00 29. .98 C

ATOM 874 C ASN A1097 -6, .020 28. .161 2. .582 1. ,00 28. .76 C

ATOM 875 O ASN A1097 -6, .938 28. .893 2. .210 1. ,00 28. .83 O

ATOM 876 CB ASN A1097 -7, .723 26. .366 3. .037 1. ,00 30. .63 C

ATOM 877 CG ASN A1097 -8, .174 26. .923 4. .372 1. ,00 31. .60 C

ATOM 878 OD1 ASN A1097 -7, .360 27. .193 5. .260 1. ,00 29. .68 0

ATOM 879 ND2 ASN A1097 -9, .483 27. .098 4. .523 1. ,00 33. .08 N

ATOM 880 N ASN A1098 -4, .802 28. .619 2. .867 1. ,00 27. .22 N

ATOM 881 CA ASN A1098 -4, .466 30. .037 2. .738 1. ,00 25. .84 C

ATOM 882 C ASN A1098 -4, .666 30. .426 1. ,273 1. 00 25. .56 C

ATOM 883 O ASN A1098 -4. .135 29. ,771 0. .375 1. 00 26. .17 O

ATOM 884 CB ASN A1098 -3. ,010 30. ,280 3. .165 1. 00 23. .84 C

ATOM 885 CG ASN A1098 -2. .651 31. ,757 3. .227 1. 00 22. .49 C

ATOM 886 ODl ASN A1098 -2. .465 32. ,410 2. .199 1. 00 24. ,26 O

ATOM 887 ND2 ASN A1098 -2. .529 32. ,283 4. .439 1. 00 20. .21 N

ATOM 888 N PRO A1099 -5. .442 31. ,491 1. ,013 1. 00 26. ,13 N

ATOM 889 CA PRO A1099 -5. ,727 31. ,971 -0. ,347 1. 00 26. 13 C

ATOM 890 C PRO A1099 -4. ,588 32. ,688 -1. .073 1. 00 26. 31 C

ATOM 891 O PRO A1099 -4, .740 33. .083 -2. .228 1. 00 26. ,27 0

< ATOM 892 CB PRO A1099 -6.921 32.900 -0.130 1.00 26.04 C

ATOM 893 CG PRO A1099 -6 .640 33 .475 1 .210 1 .00 23 .35 C

ATOM 894 CD PRO A1099 -6 .188 32 .279 2 .012 1 .00 24 .27 C

ATOM 895 N GLY A1100 -3 .457 32 .857 -0 .397 1 .00 27 .95 N

ATOM 896 CA GLY A1100 -2 .317 33 .516 -1 .011 1 .00 27 .48 C

ATOM 897 C GLY A1100 -2 .299 35 .020 -0 .841 1 .00 28 .03 C

ATOM 898 O GLY A1100 -1 .838 35 .742 -1 .724 1 .00 29 .12 0

ATOM 899 N ARG A1101 -2 .845 35 .496 0 .272 1 .00 27 .08 N

ATOM 900 CA ARG A1101 -2 .859 36 .921 0 .574 1 .00 26 .03 C

ATOM 901 C ARG A1101 -2 .620 37 .087 2 .067 1 .00 23 .60 C

ATOM 902 O ARG A1101 -2 .839 36 .154 2 .840 1 .00 23 .84 O

ATOM 903 CB ARG A1101 -4 .179 37 .579 0. .153 1 .00 27 .68 C

ATOM 904 CG ARG A1101 -5 .416 37 .063 0 .859 1 .00 28 .83 C

ATOM 905 CD ARG A1101 -6 .418 38 .187 1 .060 1 .00 32 .05 C

ATOM 906 NE ARG A1101 -5 .985 39 .087 2 .129 1 .00 35 .41 N

ATOM 907 CZ ARG A1101 -6 .037 40 .415 2. .075 1 .00 34 .66 C

ATOM 908 NHl ARG A1101 -6 .509 41 .024 0 .994 1 .00 34 .63 N

ATOM 909 NH2 ARG A1101 -5 .600 41 .133 3, .103 1 .00 33 .43 N

ATOM 910 N PRO A1102 -2 .162 38 .270 2 .496 1 .00 23 .72 N

ATOM 911 CA PRO A1102 -1 .880 38, .554 3, .907 1, .00 20 .98 C

ATOM 912 C PRO A1102 -3 .125 38, .612 4 .787 1 .00 21 .00 C

ATOM 913 O PRO A1102 -4 .249 38 .671 4 .287 1 .00 20 .29 O

ATOM 914 CB PRO A1102 -1 .212 39, .936 3, .854 1, .00 21 .71 C

ATOM 915 CG PRO A1102 -0 .720 40, .061 2, .441 1 .00 22 .95 C

ATOM 916 CD PRO A1102 -1 .841 39, .450 1, .668 1, .00 22 .05 C

ATOM 917 N PRO A1103 -2. .941 38, .546 6, .116 1, .00 20 .75 N

ATOM 918 CA PRO A1103 -4 .091 38, .621 7, .021 1 .00 19 .13 C

ATOM 919 C PRO A1103 -4 .630 40, .049 6, .879 1, .00 18 .26 C

ATOM 920 O PRO A1103 -3 .939 40, .929 6, .349 1, .00 14 .54 O

ATOM 921 CB PRO A1103 -3, .461 38. .426 8, ,399 1. .00 19, .19 C

ATOM 922 CG PRO A1103 -2 .233 37. .655 8, .130 1, .00 22 .73 C

ATOM 923 CD PRO A1103 -1 .704 38, .266 6, .865 1, ,00 20 .33 C

ATOM 924 N PRO A1104 -5, .840 40. .317 7. .388 1. .00 16, .61 N

ATOM 925 CA PRO A1104 -6, .423 41. .660 7. .285 1, .00 16 .35 C

ATOM 926 C PRO A1104 -5 .537 42, .806 7, .812 1, .00 15 .79 C

ATOM 927 O PRO A1104 -5, .014 42. .733 8. .928 1. .00 14, .91 O

ATOM 928 CB PRO A1104 -7, .703 41. .537 8. .119 1. .00 17, .87 C

ATOM 929 CG PRO A1104 -8, .060 40. .077 7. .994 1. .00 18, .13 C

ATOM 930 CD PRO A1104 -6, .719 39. .422 8. .163 1. .00 17, .43 C

ATOM 931 N THR A1105 -5, .380 43. ,856 7. .002 1. .00 12, .90 N

ATOM 932 CA THR A1105 -4, .606 45. ,040 7. .396 1. .00 13, .47 C

ATOM 933 C THR A1105 -5, ,508 45. .867 8. .330 1. .00 12, .83 C

ATOM 934 O THR A1105 -6, .695 45. ,587 8. ,447 1. .00 12, .45 O

ATOM 935 CB THR A1105 -4, .279 45. ,951 6. .190 1. .00 12, .55 C

ATOM 936 OG1 THR A1105 -5, .488 46. .529 5. ,691 1. .00 10, .77 O

ATOM 937 CG2 THR A1105 -3, .633 45. ,178 5. ,064 1. ,00 13. .27 C

ATOM 938 N LEU A1106 -4, .949 46. .888 8. .973 1. ,00 13, .75 N

ATOM 939 CA LEU A1106 -5. .728 47. ,753 9. ,862 1. ,00 13. .86 C

ATOM 940 C LEU A1106 -6. .911 48. ,356 9. ,086 1. ,00 12. .80 C

ATOM 941 O LEU A1106 -8, .042 48. .368 9. .563 1. ,00 14, ,97 O

ATOM 942 CB LEU A1106 -4. .841 48. ,870 10. ,409 1. ,00 14. .13 C

ATOM 943 CG LEU A1106 -5. .169 49. ,566 11. .738 1. .00 20. .05 C

ATOM 944 CDl LEU A1106 -4, .761 51. .023 11. ,637 1. .00 15. .18 C

ATOM 945 CD2 LEU A1106 -6. .639 49. ,447 12. ,128 1. ,00 18. .56 C

ATOM 946 N GLN A1107 -6. .630 48. ,853 7. ,888 1. 00 12, .22 N

ATOM 947 CA GLN A1107 -7. .638 49. ,441 7. ,004 1. ,00 13. ,50 C

ATOM 948 C GLN A1107 -8. .769 48. ,446 6. ,691 1. ,00 13. .49 C ATOM 949 0 GLN A1107 -9.962 48.787 6.748 1.00 12.75 O

ATOM 950 CB GLN A1107 -6 .957 49 .877 5 .702 1 .00 13 .70 C

ATOM 951 CG GLN A1107 -7 .881 50 .413 4 .616 1 .00 14 .71 C

ATOM 952 CD GLN A1107 -7 .112 50 .879 3 .397 1 .00 17 .26 C

ATOM 953 OEl GLN A1107 -6 .253 50 .163 2 .886 1 .00 16 .06 O

ATOM 954 NE2 GLN A1107 -7 .406 52 .089 2 .930 1 .00 16 .82 N

ATOM 955 N GLU A1108 -8 .389 47 .217 6 .358 1 .00 11 .48 N

ATOM 956 CA GLU A1108 -9 .370 46 .184 6 .046 1 .00 12 .61 C

ATOM 957 C GLU A1108 -10 .215 45 .824 7 .261 1 .00 11 .97 C

ATOM 958 O GLU A1108 -11 .404 45 .533 7 .123 1 .00 11 .46 0

ATOM 959 CB GLU All08 -8 .687 44, .941 5 .471 1 .00 13 .26 c

ATOM 960 CG GLU A1108 -8 .158 45 .165 4 .064 1 .00 13 .80 c

ATOM 961 CD GLU A1108 -7 .377 43 .979 3 .527 1 .00 17 .40 c

ATOM 962 OEl GLU A1108 -6 .716 43 .283 4 .324 1 .00 15 .45 0

ATOM 963 OE2 GLU A1108 -7 .421 43 .754 2 .299 1 .00 17 .62 0

ATOM 964 N MET A1109 -9 .610 45, .845 8 .446 1 .00 11 .03 N

ATOM 965 CA MET A1109 -10 .348 45 .530 9 .668 1, .00 11 .15 C

ATOM 966 C MET A1109 -11 .373 46 .612 9 .994 1 .00 11 .74 c

ATOM 967 O MET A1109 -12 .490 46, .305 10 .418 1, .00 12 .65 0

ATOM 968 CB MET A1109 -9 .390 45 .285 10 .838 1, .00 13, .17 c

ATOM 969 CG MET A1109 -8 .616 43, .970 10 .677 1, .00 15 .38 c

ATOM 970 SD MET A1109 -7 .561 43, .529 12 .058 1 .00 20 .53 s

ATOM 971 CE MET A1109 -6 .661 44, .963 12, .196 1, .00 15, .29 c

ATOM 972 N ILE A1110 -10 .994 47, .873 9 .780 1, .00 11, .81 N

ATOM 973 CA ILE A1110 -11 .887 49, .003 10 .021 1 .00 11 .17 c

ATOM 974 C ILE A1110 -13, .061 48, ,920 9, .037 1, .00 10, .21 c

ATOM 975 O ILE A1110 -14 .212 49, .138 9 .418 1, .00 11, .80 0

ATOM 976 CB ILE A1110 -11, .131 50, .367 9, .876 1, ,00 11, .29 c

ATOM 977 CGI ILE A1110 -10, .107 50, .537 11, .002 1, ,00 10, .78 c

ATOM 978 CG2 ILE A1110 -12 .109 51, .545 9 .847 1, .00 12, .20 c

ATOM 979 CDl ILE A1110 -10, .678 50. .556 12, .392 1, .00 13, .09 c

ATOM 980 N GLN Aim -12, .766 48, .590 7, .777 1, .00 9, .45 N

ATOM 981 CA GLN Aim -13, .798 48. .462 6, .739 1. .00 8. .00 C

ATOM 982 C GLN Aim -14, .808 47. .366 7, .126 1. .00 9. .98 C

ATOM 983 O GLN Aim -16, .013 47. .551 6, .991 1, .00 9, .36 O

ATOM 984 CB GLN Aim -13, .141 48. .152 5, ,385 1. .00 6. ,51 c

ATOM 985 CG GLN Aim -14, .098 48. .045 4, .200 1, .00 5, .88 c

ATOM 986 CD GLN Aim -14. .649 49. .382 3, .746 1. .00 10. .41 c

ATOM 987 OEl GLN Aim -13, .965 50. .401 3, ,795 1. ,00 11. .65 O

ATOM 988 NE2 GLN Aim -15, .888 49. .380 3. ,277 1. .00 9. .04 N

ATOM 989 N MET A1112 -14, .301 46. .231 7. .612 1. .00 9. .08 N

ATOM 990 CA MET A1112 -15, .141 45. .122 8, .052 1. .00 9. .81 C

ATOM 991 C MET A1112 -16. .028 45. .568 9. .209 1. .00 10. .76 C

ATOM 992 O MET A1112 -17, .226 45. .290 9, .231 1. .00 8. .85 O

ATOM 993 CB MET A1112 -14. .281 43. .968 8. .573 1. ,00 10. ,32 C

ATOM 994 CG MET A1112 -13. .563 43. .155 7. ,534 1. .00 14. ,59 C

ATOM 995 SD MET A1112 -12, .707 41. .788 8, ,349 1. .00 18. ,72 S

ATOM 996 CE MET A1112 -11. .822 41. .098 7. .001 1. .00 17. ,55 C

ATOM 997 N ALA A1113 -15. .416 46. .248 10. .176 1. .00 9. .32 N

ATOM 998 CA ALA A1113 -16. .125 46. .724 11. .355 1. ,00 9. ,95 C

ATOM 999 C ALA A1113 -17. ,247 47. .666 10. .963 1. .00 8. ,47 C

ATOM 1000 O ALA A1113 -18. ,341 47. .563 11. .488 1. ,00 8. ,38 O

ATOM 1001 CB ALA A1113 -15. .160 47. .418 12. .326 1. ,00 10. ,33 C

ATOM 1002 N ALA A1114 -16. .968 48. .579 10. .039 1. .00 7. ,83 N

ATOM 1003 CA ALA A1114 -17. .973 49. .541 9. .588 1. ,00 9. ,41 C

ATOM 1004 C ALA A1114 -19. .140 48. .867 8. .845 1. ,00 9. ,01 C

ATOM 1005 O ALA A1114 -20. ,290 49. .249 9. ,019 1. ,00 8. ,77 O

sr ATOM 1006 CB ALA A1114 -17.330 50.613 8.710 1.00 7.59 C

ATOM 1007 N GLU A1115 -18 .840 47 .870 8 .020 1 .00 8 .94 N

ATOM 1008 CA GLU A1115 -19. .879 47 .151 7 .279 1 .00 8 .64 C

ATOM 1009 C GLU A1115 -20 .797 46 .357 8 .210 1 .00 9 .71 C

ATOM 1010 O GLU A1115 -22 .019 46 .360 8 .047 1 .00 9 .68 0

ATOM 1011 CB GLU A1115 -19 .238 46 .229 6 .252 1 .00 11 .23 c

ATOM 1012 CG GLU A1115 -18, .503 47 .016 5 .168 1 .00 10 .73 c

ATOM 1013 CD GLU A1115 -17 .664 46 .162 4 .249 1 .00 9 .30 c

ATOM 1014 OEl GLU A1115 -17 .305 45 .033 4 .620 1 .00 9 .67 0

ATOM 1015 OE2 GLU A1115 -17 .333 46 .650 3 .148 1 .00 12 .69 O

ATOM 1016 N ILE A1116 -20 .193 45 .679 9 .183 1 .00 7 .89 N

ATOM 1017 CA ILE A1116 -20 .938 44 .888 10 .158 1 .00 6 .65 c

ATOM 1018 C ILE A1116 -21 .788 45 .849 11 .000 1 .00 8 .11 C

ATOM 1019 O ILE A1116 -22 .964 45 .580 11 .258 1 .00 8 .56 O

ATOM 1020 CB ILE A1116 -19 .970 44 .094 11 .087 1 .00 7 .59 C

ATOM 1021 CGI ILE A1116 -19, .233 43 .003 10 .298 1 .00 4 .58 c

ATOM 1022 CG2 ILE A1116 -20 .726 43 .487 12 .267 1 .00 9 .82 c

ATOM 1023 CDl ILE A1116 -18, .035 42, .391 11 .052 1, .00 9 .78 c

ATOM 1024 N ALA A1117 -21 .191 46 .968 11 .421 1 .00 6 .98 N

ATOM 1025 CA ALA A1117 -21, .904 47 .952 12 .240 1, .00 6 .34 C

ATOM 1026 C ALA A1117 -23 .054 48 .621 11 .484 1 .00 8 .46 C

ATOM 1027 O ALA A1117 -24, .081 48, .943 12, .074 1, .00 10, .85 O

ATOM 1028 CB ALA A1117. -20, .934 49 .011 12 .784 1, .00 6 .16 C

ATOM 1029 N ASP A1118 -22, .878 48. .826 10. .180 1, .00 8. .29 N

ATOM 1030 CA ASP A1118 -23, .910 49 .446 9, .352 1 .00 9, .05 c

ATOM 1031 C ASP A1118 -25, .081 48 .477 9 .179 1 .00 9, .46 c

ATOM 1032 O ASP A1118 -26, .252 48, .868 9, .267 1, .00 8, .08 0

ATOM 1033 CB ASP A1118 -23, .323 49 .827 7 .987 1 .00 8 .01 c

ATOM 1034 CG ASP A1118 -24, .295 50, .621 7, .137 1, .00 12, .91 c

ATOM 1035 OD1 ASP A1118 -24, .635 51, .753 7, .534 1, .00 10, .74 0

ATOM 1036 OD2 ASP A1118 -24. .720 50, .116 6, .073 1, .00 7, .80 0

ATOM 1037 N GLY A1119 -24, .759 47, .209 8 .931 1, .00 7, .75 N

ATOM 1038 CA GLY A1119 -25. .795 46, .209 8, .768 1, .00 8, .25 C

ATOM 1039 C GLY A1119 -26, .565 46, .079 10, .066 1, .00 9, .74 C

ATOM 1040 O GLY A1119 -27. .796 45. .989 10, ,055 1. .00 11. .23 O

ATOM 1041 N MET A1120 -25. .843 46, .091 11, .186 1, .00 7, .81 N

ATOM 1042 CA MET A1120 -26, .470 45, .982 12, .498 1, .00 10. .16 C

ATOM 1043 C MET A1120 -27. .308 47, .221 12, ,805 1, .00 9, .79 C

ATOM 1044 O MET A1120 -28. .358 47, .119 13, ,433 1. .00 9, .64 O

ATOM 1045 CB MET A1120 -25. .420 45, .739 13, .593 1. .00 10. .02 C

ATOM 1046 CG MET A1120 -24. .802 44, .345 13, .569 1, .00 9. .79 C

ATOM 1047 SD MET A1120 -26. ,021 43. .005 13. .705 1. .00 9. ,78 S

ATOM 1048 CE MET A1120 -26. ,638 43, .317 15, .323 1, .00 10. ,15 C

ATOM 1049 N ALA A1121 -26. .846 48, .384 12, .351 1. .00 9. ,98 N

ATOM 1050 CA ALA A1121 -27. .576 49, .638 12, .559 1. .00 9. .35 C

ATOM 1051 C ALA A1121 -28, .944 49. .543 11. .871 1. .00 10. ,12 C

ATOM 1052 O ALA A1121 -29. .974 49. .930 12, ,438 1. .00 11. .78 O

ATOM 1053 CB ALA A1121 -26. ,783 50. ,813 11, ,982 1. ,00 8. .90 C

ATOM 1054 N TYR A1122 -28. ,937 49. ,023 10. .649 1. .00 8. ,24 N

ATOM 1055 CA TYR A1122 -30. .152 48, .844 9, ,862 1. .00 9. ,67 C

ATOM 1056 C TYR A1122 -31. ,125 47. .927 10. .603 1. .00 12. .18 C

ATOM 1057 O TYR A1122 -32. ,304 48. .249 10, .754 1. .00 12. .16 O

ATOM 1058 CB TYR A1122 -29. ,792 48. .258 8. .497 1. .00 10. .07 C

ATOM 1059 CG TYR A1122 -30. .990 47. .889 7. .667 1. .00 12. .50 c

ATOM 1060 CDl TYR A1122 -31. ,676 48. .856 6. .927 1. ,00 16. ,00 c

ATOM 1061 CD2 TYR A1122 -31. .482 46. ,585 7. .668 1. ,00 13. ,52 c

ATOM 1062 CE1 TYR A1122 -32. ,825 48. ,534 6. .217 1. ,00 14. ,89 c ATOM 1063 CE2 TYR A1122 -32.630 46.253 6.965 1.00 13.06 C

ATOM 1064 CZ TYR A1122 -33 .298 47 .230 6 .246 1 .00 16 .45 C

ATOM 1065 OH TYR A1122 -34 .450 46 .906 5 .577 1 .00 13 .99 O

ATOM 1066 N LEU A1123 -30 .616 46 .789 11 .070 1 .00 12 .09 N

ATOM 1067 CA LEU A1123 -31 .415 45 .816 11 .804 1 .00 12 .76 C

ATOM 1068 C LEU A1123 -32 .056 46 .477 13 .032 1 .00 14 .11 C

ATOM 1069 O LEU A1123 -33 .255 46 .303 13 .284 1 .00 10 .68 O

ATOM 1070 CB LEU A1123 -30 .528 44 .623 12 .189 1 .00 18 .16 C

ATOM 1071 CG LEU A1123 -31 .147 43 .315 12 .677 1 .00 23 .59 C

ATOM 1072 CDl LEU A1123 -30 .442 42 .156 11 .995 1 .00 26 .33 C

ATOM 1073 CD2 LEU A1123 -31 .023 43 .193 14 .188 1 .00 26 .46 C

ATOM 1074 N ASN A1124 -31 .256 47 .245 13 .775 1 .00 9 .41 N

ATOM 1075 CA ASN A1124 -31 .731 47 .964 14 .958 1 .00 12 .83 C

ATOM 1076 C ASN A1124 -32 .812 48 .980 14 .592 1 .00 12 .34 C

ATOM 1077 O ASN A1124 -33 .783 49 .151 15 .336 1 .00 13 .03 O

ATOM 1078 CB ASN A1124 -30 .575 48 .698 15 .653 1 .00 12 .56 c

ATOM 1079 CG ASN A1124 -31 .045 49 .570 16 .818 1 .00 18 .28 c

ATOM 1080 ODl ASN A1124 -30 .934 50 .807 16 .786 1 .00 20 .90 0

ATOM 1081 ND2 ASN A1124 -31 .577 48 .933 17 .847 1 .00 17 .10 N

ATOM 1082 N ALA A1125 -32 .630 49 .646 13, .452 1 .00 12 .08 N

ATOM 1083 CA ALA A1125 -33 .577 50 .647 12 .961 1 .00 12 .52 C

ATOM 1084 C ALA A1125 -34 .912 50 .007 12 .600 1 .00 13 .88 C

ATOM 1085 O ALA A1125 -35 .966 50 .634 12, .720 1. .00 13 .08 O

ATOM 1086 CB ALA A1125 -33 .002 51 .380 11 .746 1 .00 12 .79 C

ATOM 1087 N LYS A1126 -34 .865 48, .758 12, .156 1, .00 9, .90 N

ATOM 1088 CA LYS A1126 -36 .082 48, .035 11, .792 1, .00 13, .04 C

ATOM 1089 C LYS A1126 -36 .734 47 .439 13 .040 1 .00 13 .05 C

ATOM 1090 O LYS A1126 -37 .750 46, .744 12, ,959 1, .00 13, .27 O

ATOM 1091 CB LYS A1126 -35 .756 46 .937 10, .778 1, .00 14 .09 C

ATOM 1092 CG LYS A1126 -35 .162 47. .473 9, .490 1, .00 16 .31 C

ATOM 1093 CD LYS A1126 -36, .162 48, .339 8, .723 1, .00 20, .79 C

ATOM 1094 CE LYS A1126 -37 .137 47, .462 7, .941 1. .00 26 .86 C

ATOM 1095 NZ LYS A1126 -38, .190 48, .228 7. .215 1. .00 28, .83 N

ATOM 1096 N LYS A1127 -36, .129 47, .722 14, .191 1, .00 10, .75 N

ATOM 1097 CA LYS A1127 -36 .586 47 .252 15, ,492 1, .00 13 .72 C

ATOM 1098 C LYS A1127 -36, .501 45, .737 15. .690 1, .00 14, .99 c

ATOM 1099 O LYS A1127 -37, .485 45, .070 16, .031 1, .00 15, .15 0

ATOM 1100 CB LYS A1127 -37, .989 47, .793 15. .812 1. .00 18. .57 c

ATOM 1101 CG LYS A1127 -38, .018 49, .302 16. .045 1, .00 17, ,27 c

ATOM 1102 CD LYS A1127 -37, .278 49, .664 17, .326 1, .00 24, ,30 c

ATOM 1103 CE LYS A1127 -37, .100 51, .170 17. .454 1. .00 24, .59 c

ATOM 1104 NZ LYS A1127 -36, ,374 51, .536 18. .695 1. .00 28, .11 N

ATOM 1105 N PHE A1128 -35. .300 45. .208 15. .466 1. .00 14, .35 N

ATOM 1106 CA PHE A1128 -35, .010 43, .794 15. .666 1. .00 14, .14 c

ATOM 1107 C PHE A1128 -33, .695 43, .706 16. .417 1. .00 15, .68 c

ATOM 1108 O PHE A1128 -32, .833 44. .582 16. .280 1. .00 14. .79 0

ATOM 1109 CB PHE A1128 -34, .840 43, .050 14. .344 1. .00 15. .06 c

ATOM 1110 CG PHE A1128 -36. .116 42. .829 13. .602 1. .00 13. .97 c

ATOM 1111 CDl PHE A1128 -36, .944 41. .757 13. ,923 1. .00 12. .58 c

ATOM 1112 CD2 PHE A1128 -36, .492 43, .689 12. .576 1. .00 12, .99 c

ATOM 1113 CE1 PHE A1128 -38. .132 41. .548 13. ,228 1. .00 14. .79 c

ATOM 1114 CE2 PHE A1128 -37, ,679 43. .487 11. .876 1. ,00 15. .77 c

ATOM 1115 CZ PHE A1128 -38, .499 42, .416 12. .203 1. .00 15, ,68 c

ATOM 1116 N VAL A1129 -33. .553 42. .651 17, ,208 1. .00 13. .49 N

ATOM 1117 CA VAL A1129 -32, .326 42. .396 17. .946 1. .00 12. ,04 c

ATOM 1118 C VAL A1129 -31. .851 41. .049 17. ,389 1. .00 12. ,58 c

ATOM 1119 O VAL A1129 -32. .620 40. .081 17. ,323 1. .00 10. .25 0 ATOM 1120 CB VAL A1129 -32.555 42.406 19.497 1.00 14.66 C

ATOM 1121 CGI VAL A1129 -33 .553 41 .340 19 .921 1 .00 15 .26 C

ATOM 1122 CG2 VAL A1129 -31 .230 42 .235 20 .230 1 .00 12 .99 C

ATOM 1123 N HIS A1130 -30 .593 41 .003 16 .964 1 .00 10 .01 N

ATOM 1124 CA HIS A1130 -30 .020 39 .813 16 .350 1 .00 8 .97 C

ATOM 1125 C HIS A1130 -29 .846 38 .628 17 .301 1 .00 9 .92 C

ATOM 1126 O HIS A1130 -30 .242 37 .511 16 .978 1 .00 9 .78 0

ATOM 1127 CB HIS A1130 -28 .682 40 .174 15 .705 1 .00 10 .84 c

ATOM 1128 CG HIS A1130 -28 .174 39 .139 14 .757 1 .00 10 .64 c

ATOM 1129 NDl HIS A1130 -27 .611 37 .956 15 .178 1 .00 10 .88 N

ATOM 1130 CD2 HIS A1130 -28 .111 39 .126 13 .406 1 .00 9 .37 C

ATOM 1131 CE1 HIS A1130 -27 .208 37 .262 14 .130 1 .00 8 .61 C

ATOM 1132 NE2 HIS A1130 -27 .503 37 .950 13 .041 1 .00 10 .89 N

ATOM 1133 N ARG A1131 -29 .232 38 .899 18 .452 1 .00 10 .40 N

ATOM 1134 CA ARG A1131 -28 .970 37 .936 19 .520 1 .00 11 .40 C

ATOM 1135 C ARG A1131 -27 .901 36 .885 19 .255 1 .00 10 .02 C

ATOM 1136 O ARG A1131 -27 .543 36 .135 20 .163 1 .00 11 .17 0

ATOM 1137 CB ARG A1131 -30 .257 37 .240 19 .953 1 .00 13 .41 c

ATOM 1138 CG ARG A1131 -31 .348 38 .209 20 .439 1 .00 13 .96 c

ATOM 1139 CD ARG A1131 -32 .615 37 .437 20 .738 1, .00 16 .20 c

ATOM 1140 NE ARG A1131 -32 .408 36 .474 21 .807 1, .00 19 .93 N

ATOM 1141 CZ ARG A1131 -32 .768 35 .195 21 .763 1 .00 16 .89 c

ATOM 1142 NHl ARG A1131 -33 .362 34 .683 20 .691 1, .00 16, .22 N

ATOM 1143 NH2 ARG A1131 -32 .547 34 .435 22 .821 1, .00 15 .90 N

ATOM 1144 N ASP A1132 -27, .387 36, .821 18 .033 1, .00 7, .92 N

ATOM 1145 CA ASP A1132 -26, .371 35, .829 17 .712 1. .00 9, .87 C

ATOM 1146 C ASP A1132 -25, .296 36 .396 16 .772 1, .00 8, .43 C

ATOM 1147 O ASP A1132 -24, .860 35, .729 15, .831 1. .00 8, .31 0

ATOM 1148 CB ASP A1132 -27, .048 34, .577 17 .125 1. .00 6. .94 C

ATOM 1149 CG ASP A1132 -26, .153 33, .336 17, .161 1. .00 13, .41 c

ATOM 1150 ODl ASP A1132 -25, .148 33, ,311 17, .898 1. .00 11. .42 0

ATOM 1151 OD2 ASP A1132 -26, .467 32, .378 16, .423 1. .00 11, .86 0

ATOM 1152 N LEU A1133 -24. .876 37. .635 17, .023 1. .00 9. .24 N

ATOM 1153 CA LEU A1133 -23. .829 38. .255 16, ,203 1. .00 9. .70 c

ATOM 1154 C LEU A1133 -22, .505 37, .602 16, .605 1. .00 8. .97 c

ATOM 1155 O LEU A1133 -22. .148 37. .564 17. .784 1. ,00 6. .96 0

ATOM 1156 CB LEU A1133 -23. .769 39. .780 16. .415 1. ,00 10. .26 c

ATOM 1157 CG LEU A1133 -22. .661 40. ,537 15. .664 1. ,00 9. .89 c

ATOM 1158 CDl LEU A1133 -22. .790 40. .326 14. .149 1. ,00 8. .93 c

ATOM 1159 CD2 LEU A1133 -22. .741 42. ,028 16. .001 1. ,00 8. .20 c

ATOM 1160 N ALA A1134 -21. ,795 37. .085 15. .607 1. ,00 10. ,55 N

ATOM 1161 CA ALA A1134 -20. .532 36. ,393 15. .808 1. ,00 8. ,22 C

ATOM 1162 C ALA A1134 -19. ,887 36. ,263 14. ,431 1. 00 7. ,86 C

ATOM 1163 O ALA A1134 -20. ,583 36. ,346 13. .420 1. ,00 6. ,15 O

ATOM 1164 CB ALA A1134 -20. .801 35. ,011 16. .398 1. 00 9. ,22 c

ATOM 1165 N ALA A1135 -18. ,572 36. ,054 14. ,376 1. 00 8. ,46 N

ATOM 1166 CA ALA A1135 -17. ,896 35. ,934 13. .085 1. ,00 8. ,40 C

ATOM 1167 C ALA A1135 -18. .481 34. ,811 12. .226 1. 00 9. ,09 C

ATOM 1168 O ALA A1135 -18. ,561 34. ,940 11. ,008 1. 00 8. ,41 O

ATOM 1169 CB ALA A1135 -16. ,383 35. ,756 13. ,263 1. ,00 7. ,75 c

ATOM 1170 N ARG A1136 -18. 905 33. 717 12. ,861 1. 00 10. 52 N

ATOM 1171 CA ARG A1136 -19. ,489 32. ,586 12. ,129 1. 00 9. ,91 C

ATOM 1172 C ARG A1136 -20. ,777 33. ,004 11. ,406 1. 00 10. ,77 C

ATOM 1173 O ARG A1136 -21. 155 32. 413 10. ,399 1. 00 11. 85 O

ATOM 1174 CB ARG A1136 -19. ,797 31. ,423 13. ,092 1. 00 8. 20 C

ATOM 1175 CG ARG A1136 -20. 818 31. 772 14. ,180 1. 00 7. 99 c

ATOM 1176 CD ARG A1136 -21. 147 30. 602 15. ,100 1. 00 9. 65 c

^ ATOM 1177 NE ARG A1136 -22.060 31.022 16.172 1.00 13.96 N

ATOM 1178 CZ ARG A1136 -21 .677 31 .596 17 .313 1 .00 12 .89 C

ATOM 1179 NHl ARG A1136 -20 .389 31 .814 17 .557 1 .00 11 .26 N

ATOM 1180 NH2 ARG A1136 -22 .582 32 .044 18 .170 1 .00 9 .06 N

ATOM 1181 N ASN A1137 -21 .431 34 .039 11 .928 1 .00 11 .64 N

ATOM 1182 CA ASN A1137 -22 .684 34 .531 11 .369 1 .00 10 .97 C

ATOM 1183 c ASN A1137 -22 .596 35 .761 10 .480 1 .00 10 .46 C

ATOM 1184 O ASN A1137 -23 .614 36 .306 10 .071 1 .00 10 .52 O

ATOM 1185 CB ASN A1137 -23 .718 34 .691 12 .488 1 .00 10 .26 C

ATOM 1186 CG ASN A1137 -24 .148 33 .347 13 .056 1 .00 10 .51 C

ATOM 1187 OD1 ASN A1137 -24 .065 32 .334 12 .366 1 .00 13 .23 O

ATOM 1188 ND2 ASN A1137 -24 .571 33 .321 14 .313 1 .00 10 .38 N

ATOM 1189 N CYS A1138 -21 .374 36 .199 10 .191 1 .00 8 .25 N

ATOM 1190 CA CYS A1138 -21 .152 37 .312 9 .272 1 .00 11 .20 C

ATOM 1191 C CYS A1138 -20 .624 36 .599 8 .028 1 .00 10 .92 C

ATOM 1192 O CYS A1138 -19 .865 35 .641 8 .155 1 .00 10 .50 O

ATOM 1193 CB CYS A1138 -20 .098 38 .292 9 .812 1 .00 12 .09 C

ATOM 1194 SG CYS A1138 -20 .617 39 .232 11 .259 1 .00 12 .82 S

ATOM 1195 N MET A1139 -21 .028 37 .050 6 .843 1 .00 10 .30 N

ATOM 1196 CA MET A1139 -20 .593 36 .436 5 .590 1 .00 11 .16 C

ATOM 1197 C MET A1139 -19 .716 37 .390 4 .771 1 .00 9 .90 C

ATOM 1198 O MET A1139 -19 .824 38 .603 4 .900 1 .00 9 .46 O

ATOM 1199 CB MET A1139 -21 .807 35 .987 4 .769 1 .00 10 .43 c

ATOM 1200 CG MET A1139 -22 .789 35 .071 5 .507 1 .00 14 .39 c

ATOM 1201 SD MET A1139 -22 .110 33 .447 5 .864 1 .00 17 .76 s

ATOM 1202 CE MET A1139 -22 .635 33 .219 7 .520 1. .00 19 .91 c

ATOM 1203 N VAL A1140 -18 .854 36 .825 3 .925 1, .00 9. .98 N

ATOM 1204 CA VAL A1140 -17 .915 37 .597 3 .110 1, .00 11 .20 C

ATOM 1205 C VAL A1140 -18, .197 37 .381 1 .623 1. .00 11, .78 C

ATOM 1206 O VAL A1140 -18, .230 36 .245 1, .138 1, .00 12, .63 O

ATOM 1207 CB VAL A1140 -16, .440 37, .201 3, .457 1, .00 9, .83 C

ATOM 1208 CGI VAL A1140 -15, .447 38, .115 2, .774 1. .00 10, .79 C

ATOM 1209 CG2 VAL A1140 -16. .234 37, .239 4, .967 1. .00 7, .18 c

ATOM 1210 N ALA A1141 -18. .400 38, .489 0, .909 1. ,00 11. .45 N

ATOM 1211 CA ALA A1141 -18. .708 38. .468 -0. .516 1. ,00 13. .17 C

ATOM 1212 C ALA A1141 -17. .484 38. .329 -1^'. .410 1. ,00 15. .22 C

ATOM 1213 O ALA A1141 -16. .346 38. .389 -0. .937 1. ,00 16. .49 O

ATOM 1214 CB ALA All41 -19. .503 39. .725 -0. .903 1. 00 13. ,53 C

ATOM 1215 N HIS A1142 -17. .730 38. ,149 -2. .705 1. 00 14. ,90 N

ATOM 1216 CA HIS A1142 -16. ,651 38. .010 -3. .681 1. 00 18. ,29 C

ATOM 1217 C HIS A1142 -15. ,685 39. ,198 -3. ,616 1. 00 18. ,57 C

ATOM 1218 O HIS A1142 -14. ,481 39. ,031 -3. ,797 1. 00 17. ,78 O

ATOM 1219 CB HIS A1142 -17. ,220 37. ,858 -5. ,104 1. 00 19. 21 C

ATOM 1220 CG HIS A1142 -17. ,936 39. ,074 -5. ,606 1. 00 25. 66 C

ATOM 1221 NDl HIS A1142 -17. ,288 40. ,107 -6. ,250 1. 00 29. 84 N

ATOM 1222 CD2 HIS A1142 -19. ,242 39. ,430 -5. ,546 1. 00 28. 95 C

ATOM 1223 CEl HIS A1142 -18. ,162 41. ,047 -6. ,563 1. 00 29. 62 C

ATOM 1224 NΞ2 HIS A1142 -19. 354 40. ,661 -6. ,147 1. 00 30. 56 N

ATOM 1225 N ASP A1143 -16. 215 40. 393 -3. 358 1. 00 18. 31 N

ATOM 1226 CA ASP A1143 -15. 377 41. 584 -3. 264 1. 00 17. 52 C

ATOM 1227 C ASP A1143 -14. 919 41. 881 -1. 835 1. 00 17. 24 C

ATOM 1228 O ASP A1143 -14. 424 42. 975 -1. 543 1. 00 17. 79 O

ATOM 1229 CB ASP A1143 -16. 086 42. 801 -3. 884 1. 00 17. 16 C

ATOM 1230 CG ASP A1143 -17. 325 43. 240 -3. 114 1. 00 17. 97 C

ATOM 1231 OD1 ASP A1143 -17. 707 42. 601 -2. 112 1. 00 16. 15 O

ATOM 1232 OD2 ASP A1143 -17. 916 44. 257 -3. 517 1. 00 18. 44 O

ATOM 1233 N PHE A1144 -15. 100 40. 893 -0. 960 1. 00 14. 37 N

J ATOM 1234 CA PHE A1144 -14.718 40.954 0.453 1.00 14.22 C

ATOM 1235 C PHE A1144 -15 .608 41 .783 1 .385 1 .00 14 .16 C

ATOM 1236 O PHE A1144 -15 .261 42 .019 2 .550 1 .00 13 .87 O

ATOM 1237 CB PHE A1144 -13 .237 41 .314 0 .590 1 .00 18 .08 C

ATOM 1238 CG PHE A1144 -12 .343 40 .409 -0 .206 1 .00 19 .78 C

ATOM 1239 CDl PHE A1144 -12 .183 39 .075 0 .162 1 .00 17 .80 C

ATOM 1240 CD2 PHE A1144 -11 .748 40 .858 -1 .384 1 .00 22 .70 C

ATOM 1241 CE1 PHE A1144 -11 .447 38 .197 -0 .639 1 .00 17 .67 C

ATOM 1242 CE2 PHE A1144 -11 .011 39 .990 -2 .190 1 .00 24 .36 C

ATOM 1243 CZ PHE A1144 -10 .863 38 .655 -1 .815 1 .00 22 .33 C

ATOM 1244 N THR A1145 -16 .762 42 .211 0 .877 1 .00 14 .37 N

ATOM 1245 CA THR A1145 -17 .712 42 .962 1 .694 1 .00 12 .21 C

ATOM 1246 C THR A1145 -18 .300 41 .990 2 .718 1 .00 11 .38 C

ATOM 1247 O THR A1145 -18. .662 40 .863 2 .382 1 .00 13 .49 0

ATOM 1248 CB THR A1145 -18 .865 43 .538 0 .837 1 .00 9 .73 c

ATOM 1249 OG1 THR A1145 -18 .330 44 .424 -0 .150 1 .00 13 .10 0

ATOM 1250 CG2 THR A1145 -19 .859 44 .314 1 .708 1 .00 12 .50 c

ATOM 1251 N VAL A1146 -18 .388 42 .435 3 .965 1 .00 9 .22 N

ATOM 1252 CA VAL A1146 -18 .939 41 .626 5 .039 1 .00 7 .97 C

ATOM 1253 C VAL A1146 -20. .398 42 .045 5 .241 1 .00 10 .21 c

ATOM 1254 O VAL A1146 -20 .728 43 .230 5 .162 1 .00 10 .17 O

ATOM 1255 CB VAL A1146 -18 .130 41 .834 6 .338 1 .00 8 .59 c

ATOM 1256 CGI VAL A1146 -18, .659 40 .929 7 .465 1 .00 5 .42 c

ATOM 1257 CG2 VAL A1146 -16 .643 41 .557 6 .067 1 .00 8 .48 c

ATOM 1258 N LYS A1147 -21 .263 41 .065 5 .482 1 .00 8 .66 N

ATOM 1259 CA LYS A1147 -22, .687 41 .310 5 .683 1, .00 8 .23 C

ATOM 1260 C LYS A1147 -23 .212 40 .437 6, .825 1 .00 9 .48 C

ATOM 1261 O LYS A1147 -22, .687 39, .354 7, .093 1, .00 12 .62 O

ATOM 1262 CB LYS A1147 -23, .469 40, .995 4, .399 1, .00 3 .83 c

ATOM 1263 CG LYS A1147 -22, .975 41 .756 3 .174 1 .00 7 .24 c

ATOM 1264 CD LYS A1147 -23, .812 41, .486 1, .934 1, .00 8 .42 c

ATOM 1265 CE LYS A1147 -23, .213 42, .206 0, .732 1. .00 7 .79 c

ATOM 1266 NZ LYS A1147 -24. .208 42, .417 -0, .346 1. .00 6, .58 N

ATOM 1267 N ILE A1148 -24. .254 40, .914 7, .492 1, .00 9 .54 N

ATOM 1268 CA ILE A1148 -24, .868 40, .183 8, .602 1, .00 9 .74 C

ATOM 1269 C ILE A1148 -25. .752 39. .047 8. .085 1, .00 11, .54 C

ATOM 1270 O ILE A1148 -26. .546 39, .230 7, ,162 1, .00 12, .48 O

ATOM 1271 CB ILE A1148 -25. .769 41. .106 9. .442 1. .00 11, .47 C

ATOM 1272 CGI ILE A1148 -25. .039 42. .411 9, .756 1. .00 11, .09 C

ATOM 1273 CG2 ILE A1148 -26. .189 40. .401 10. .723 1. .00 12. .75 C

ATOM 1274 CDl ILE A1148 -23. .806 42. ,239 10. .623 1. .00 6, .15 C

ATOM 1275 N GLY A1149 -25. .606 37. .877 8. .696 1. .00 12, .31 N

ATOM 1276 CA GLY A1149 -26. .407 36. .727 8. .322 1. .00 12. .60 C

ATOM 1277 C GLY A1149 -26. .959 36. .033 9. .554 1. .00 13, .07 C

ATOM 1278 O GLY A1149 -26. ,864 36. .560 10. .669 1. ,00 11. .80 O

ATOM 1279 N ASP A1150 -27. .502 34. .831 9. .348 1. .00 13. ,22 N

ATOM 1280 CA ASP A1150 -28. .102 34. .009 10. .397 1. .00 11, .26 C

ATOM 1281 C ASP A1150 -29. ,071 34. .737 11. ,319 1. ,00 12. .94 c

ATOM 1282 O ASP A1150 -28. .709 35. .193 12. .407 1. .00 15. .02 0

ATOM 1283 CB ASP A1150 -27. ,042 33. .267 11. ,218 1. ,00 11. .05 c

ATOM 1284 CG ASP A1150 -27. ,617 32. .062 11, ,972 1. ,00 13. ,18 c

ATOM 1285 ODl ASP A1150 -28. .855 31. .931 12. .061 1. ,00 14. ,14 0

ATOM 1286 OD2 ASP A1150 -26. ,830 31. .234 12. ,476 1. ,00 12. .11 0

ATOM 1287 N PHE A1151 -30. ,322 34. .826 10. .885 1. .00 13. .00 N

ATOM 1288 CA PHE A1151 -31, .328 35. ,511 11. ,671 1. ,00 10. ,34 c

ATOM 1289 C PHE A1151 -32. ,201 34. .545 12. ,443 1. ,00 11. .73 c

ATOM 1290 O PHE A1151 -33. ,333 34. ,868 12. ,805 1. ,00 10. ,83 0

Λ" ATOM 1291 CB PHE A1151 -32.131 36.440 10.771 1.00 13.38 C

ATOM 1292 CG PHE A1151 -31 .277 37 .433 10 .043 1 .00 10 .10 C

ATOM 1293 CDl PHE A1151 -30. .754 38 .533 10 .711 1 .00 12 .16 C

ATOM 1294 CD2 PHE A1151 -30 .930 37 .234 8 .714 1 .00 12 .07 C

ATOM 1295 CΞ1 PHE A1151 -29 .891 39 .408 10 .067 1 .00 12 .42 C

ATOM 1296 CE2 PHE A1151 -30 .067 38 .108 8 .063 1 .00 15 .46 C

ATOM 1297 CZ PHE A1151 -29 .548 39 .194 8 .741 1 .00 11 .60 C

ATOM 1298 N GLY A1152 -31 .650 33 .359 12 .709 1 .00 10 .58 N

ATOM 1299 CA GLY A1152 -32 .371 32 .339 13 .450 1 .00 13 .01 C

ATOM 1300 C GLY A1152 -32, .807 32 .776 14 .836 1, ,00 15 .32 C

ATOM 1301 O GLY A1152 -33 .919 32 .463 15 .261 1 .00 17 .21 O

ATOM 1302 N MET A1153 -31 .951 33 .514 15 .541 1 .00 14 .25 N

ATOM 1303 CA MET A1153 -32 .280 33 .979 16 .892 1, .00 13 .74 C

ATOM 1304 C MET A1153 -32 .862 35 .393 16 .955 1 .00 11 .21 C

ATOM 1305 O MET A1153 -33 .177 35 .885 18 .031 1, .00 11 .64 0

ATOM 1306 CB MET A1153 -31 .047 33 .888 17 .799 1 .00 13 .20 C

ATOM 1307 CG MET A1153 -30, .621 32 .456 18 .108 1, .00 17 .27 C

ATOM 1308 SD MET A1153 -29 .158 32 .355 19 .187 1, .00 17 .25 S

ATOM 1309 CE MET A1153 -29, .851 32 .866 20 .750 1, .00 14 .90 C

ATOM 1310 N THR A1154 -33, .008 36 .028 15 .798 1, .00 10 .61 N

ATOM 1311 CA THR A1154 -33 .513 37 .394 15 .713 1 .00 12 .63 C

ATOM 1312 C THR A1154 -34, .932 37 .550 16 .260 1, .00 13 .66 C

ATOM 1313 O THR A1154 -35 .806 36 .721 16 .003 1 .00 12 .31 O

ATOM 1314 CB THR A1154 -33, .411 37, .908 14 .261 1, .00 11, .83 C

ATOM 1315 OG1 THR A1154 -32, .037 37 .893 13 .873 1, .00 13 .53 ^' O

ATOM 1316 CG2 THR A1154 -33, .959 39, .329 14, .129 1. .00 11, .98 C

ATOM 1317 N ARG A1155 -35, .142 38, .625 17 .015 1, .00 13, .20 N

ATOM 1318 CA ARG A1155 -36, .438 38 .901 17 .622 1. .00 13 .27 C

ATOM 1319 C ARG A1155 -36, .902 40, .342 17 .410 1. .00 13, ,42 C

ATOM 1320 O ARG A1155 -36, .101 41, .275 17 .395 1, .00 11, .80 0

ATOM 1321 CB ARG A1155 -36. .385 38, .610 19, .125 1. .00 12, .80 C

ATOM 1322 CG ARG A1155 -36, ,194 37. .142 19, .477 1. .00 15, .72 C

ATOM 1323 CD ARG A1155 -37. .433 36. .310 19, .152 1. .00 17. .05 C

ATOM 1324 NE ARG A1155 -37. .276 34, ,920 19, .579 1. .00 17, .08 N

ATOM 1325 CZ ARG A1155 -36, .706 33, .971 18, .845 1. .00 12, ,14 C

ATOM 1326 NHl ARG A1155 -36. .234 34. .244 17, .635 1. .00 12. .38 N

ATOM 1327 NH2 ARG A1155 -36, .599 32, .743 19, .330 1. .00 18, .17 N

ATOM 1328 N ASP A1156 -38. .214 40. .501 17, .251 1. .00 12. .16 N

ATOM 1329 CA ASP A1156 -38. .855 41, .800 17, .058 1. .00 13. ,54 C

ATOM 1330 C ASP A1156 -38. .915 42. .520 18. .407 1. .00 14. .28 C

ATOM 1331 O ASP A1156 -39. .379 41. .952 19, .389 1, .00 18. .72 0

ATOM 1332 CB ASP A1156 -40. ,278 41. .563 16. .529 1. ,00 17. ,57 c

ATOM 1333 CG ASP A1156 -41. .002 42. .845 16. ,125 1. .00 22. .10 c

ATOM 1334 OD1 ASP A1156 -40. .581 43. .955 16, .516 1. .00 16. .56 0

ATOM 1335 OD2 ASP A1156 -42. ,021 42. .729 15. .405 1. ,00 23. .08 0

ATOM 1336 N ILE A1157 -38, ,444 43. .765 18, .466 1. .00 12. .99 N

ATOM 1337 CA ILE A1157 -38. ,474 44. .529 19. .718 1. ,00 13. .85 C

ATOM 1338 C ILE A1157 -39. .148 45. .893 19. ,528 1. .00 14. .42 C

ATOM 1339 O ILE A1157 -38. ,890 46. ,837 20. ,272 1. ,00 13. ,89 O

ATOM 1340 CB ILE A1157 -37. .048 44. .735 20. .313 1. ,00 13. .19 C

ATOM 1341 CGI ILE A1157 -36. .137 45. .416 19. .295 1. ,00 13. .24 C

ATOM 1342 CG2 ILE A1157 -36. ,466 43. .397 20. .774 1. ,00 11. .31 c

ATOM 1343 CDl ILE A1157 -34. ,835 45. .935 19. .877 1. ,00 17. .28 c

HETATM 1344 N PTR A1158 -40. ,034 45. .975 18. ,541 1. 00 16. ,15 N

HETATM 1345 CA PTR A1158 -40. ,737 47. .218 18. .216 1. ,00 18. ,91 C

HETATM 1346 C PTR A1158 -41. ,422 47. ,940 19. ,375 1. ,00 20. ,64 C

HETATM 1347 O PTR A1158 -41. ,189 49. .125 19. ,605 1. .00 23. .84 0

it HETATM 1348 CB PTR A1158 -41.780 46.962 17.124 1.00 17.84 C

HETATM 1349 CG PTR A1158 -42 .392 48 .224 16 .560 1 .00 22 .78 C

HETATM 1350 CDl PTR A1158 -41 .907 48 .787 15 .379 1 .00 24 .62 C

HETATM 1351 CD2 PTR A1158 -43 .439 48 .869 17 .217 1 .00 22 .53 C

HETATM 1352 CE1 PTR A1158 -42 .452 49 .966 14 .866 1 .00 29 .99 C

HETATM 1353 CE2 PTR A1158 -43 .990 50 .046 16 .715 1 .00 26 .31 C

HETATM 1354 CZ- PTR A1158 -43 .495 50 .589 15 .544 1 .00 31 .52 C

HETATM 1355 OH PTR A1158 -44 .055 51 .743 15 .048 1 .00 38 .18 O

HETATM 1356 P PTR A1158 -43 .439 53 .229 15 .277 1 .00 45 .28 P

HETATM 1357 OlP PTR A1158 -42 .777 53 .158 16 .607 1 .00 44 .98 0

HETATM 1358 02P PTR A1158 -44 .630 54 .126 15 .260 1 .00 45 .60 0

HETATM 1359 03P PTR A1158 -42 .534 53 .332 14 .097 1 .00 43 .26 0

ATOM 1360 N GLU A1159 -42 .270 47 .224 20 .099 1 .00 22 .77 N

ATOM 1361 CA GLU A1159 -43 .023 47 .820 21 .187 1 .00 25 .41 C

ATOM 1362 C GLU A1159 -42 .283 48 .119 22 .477 1 .00 25 .87 C

ATOM 1363 O GLU A1159 -42 .555 49 .137 23 .116 1 .00 26 .05 O

ATOM 1364 CB GLU A1159 -44 .256 46 .965 21 .495 1. .00 30 .27 C

ATOM 1365 CG GLU A1159 -45 .269 46 .867 20 .350 1 .00 38 .36 c

ATOM 1366 CD GLU A1159 -45, .947 48 .198 20 .019 1 .00 43 .44 c

ATOM 1367 OEl GLU A1159 -46 .022 49 .084 20 .905 1 .00 48 .11 0

ATOM 1368 OE2 GLU A1159 -46, .417 48 .354 18 .869 1 .00 44 .44 0

ATOM 1369 N THR A1160 -41 .346 47 .250 22 .855 1 .00 23 .62 N

ATOM 1370 CA THR A1160 -40, .624 47 .408 24 .120 1 .00 20 .79 C

ATOM 1371 C THR A1160 -39 .114 47 .681 24 .089 1 .00 20 .17 C

ATOM 1372 O THR A1160 -38, .527 47 .989 25, .125 1, .00 17 .79 O

ATOM 1373 CB THR A1160 -40, .838 46 .172 24 .994 1 .00 22 .32 C

ATOM 1374 OG1 THR A1160 -40, .230 45 .037 24, .361 1, .00 25, .59 0

ATOM 1375 CG2 THR A1160 -42, .325 45 .900 25 .178 1, .00 21 .96 c

ATOM 1376 N ASP A1161 -38, .494 47 .559 22, .919 1, .00 18, .02 N

ATOM 1377 CA ASP A1161 -37, .051 47 .771 22, .752 1, .00 19 .62 c

ATOM 1378 C ASP A1161 -36, .172 46 .707 23, .382 1, .00 18, .19 c

ATOM 1379 O ASP A1161 -34, .954 46 .870 23, .470 1, .00 18, .97 0

ATOM 1380 CB ASP A1161 -36. .617 49 .162 23, .221 1. .00 23, .85 c

ATOM 1381 CG ASP A1161 -37, ,124 50 .251 22, .315 1, ,00 27, .75 c

ATOM 1382 OD1 ASP A1161 -36. .676 50, .301 21. .152 1. ,00 31. .39 0

ATOM 1383 OD2 ASP A1161 -37, .997 51 .031 22, .751 1. ,00 33, .83 0

HETATM 1384 N PTR A1162 -36. .784 45, .616 23. ,824 1. .00 17, .33 N

HETATM 1385 CA PTR A1162 -36. .022 44 .508 24, .389 1. .00 17, .78 C

HETATM 1386 C PTR A1162 -36, .800 43 .213 24, .217 1, .00 16, .76 C

HETATM 1387 O PTR A1162 -38. .002 43 .229 23, .935 1. .00 13, .76 0

HETATM 1388 CB PTR A1162 -35. .684 44 .733 25, .872 1. .00 19, .76 c

HETATM 1389 CG PTR A1162 -36. .843 44 .520 26. .822 1. .00 22, .22 c

HETATM 1390 CDl PTR A1162 -37, .054 43 .282 27, .437 1. .00 24, .34 c

HETATM 1391 CD2 PTR A1162 -37. .747 45 .546 27. .079 1. .00 22, .15 c

HETATM 1392 CE1 PTR A1162 -38, .141 43 .078 28, .276 1. .00 27, .87 c

HETATM 1393 CE2 PTR A1162 -38. .832 45 .356 27. .913 1. ,00 25, ,93 c

HETATM 1394 CZ PTR A1162 -39, .030 44 .126 28, .507 1. .00 30, .45 c

HETATM 1395 OH PTR A1162 -40. .139 43, .962 29. .310 1, ,00 35, .83 0

HETATM 1396 P PTR A1162 -40. .245 43 .226 30, .723 1. .00 37, .01 P

HETATM 1397 OlP PTR A1162 -40. ,224 41, .789 30. .349 1. ,00 35. ,93 0

HETATM 1398 02P PTR A1162 -41. .542 43 .723 31. ,217 1. .00 42, .40 0

HETATM 1399 03P PTR A1162 -39. ,102 43, ,749 31. .508 1. ,00 38. .79 0

HETATM 1400 N PTR A1163 -36. .089 42 .103 24. .389 1. .00 13, ,40 N

HETATM 1401 CA PTR A1163 -36. ,651 40, .769 24. .298 1. ,00 16. .59 c

HETATM 1402 C PTR A1163 -36. .168 40, .026 25. .533 1. ,00 17, .96 c

HETATM 1403 O PTR A1163 -34. ,967 39, ,991 25. .809 1. ,00 17. .01 O

HETATM 1404 CB PTR A1163 -36. .155 40, .053 23. .034 1. ,00 16. .25 c

7 HETATM 1405 CG PTR A1163 -36.335 38.553 23.063 1.00 17.97 C

HETATM 1406 CDl PTR A1163 -35 .279 37 .717 23 .425 1 .00 19 .64 C

HETATM 1407 CD2 PTR A1163 -37 .566 37 .967 22 .764 1 .00 20 .56 C

HETATM 1408 CE1 PTR A1163 -35 .438 36 .345 23 .488 1 .00 22 .24 C

HETATM 1409 CΞ2 PTR A1163 -37 .736 36 .583 22 .826 1 .00 20 .91 C

HETATM 1410 CZ PTR A1163 -36 .665 35 .781 23 .191 1 .00 24 .50 C

HETATM 1411 OH PTR A1163 -36 .783 34 .411 23 .258 1 .00 31 .12 O

HETATM 1412 P PTR A1163 -38 .043 33 .403 23 .054 1 .00 33 .95 P

HETATM 1413 OlP PTR A1163 -38 .825 33 .611 24 .298 1 .00 35 .17 O

HETATM 1414 02P PTR A1163 -37 .276 32 .154 22 .967 1 .00 33 .15 O

HETATM 1415 03P PTR A1163 -38 .746 33 .803 21 .810 1 .00 32 .00 O

ATOM 1416 N ARG A1164 -37 .099 39 .446 26 .279 1 .00 16 .92 N

ATOM 1417 CA ARG A1164 -36 .752 38 .685 27 .468 1 .00 18, .82 C

ATOM 1418 C ARG A1164 -37 .015 37 .232 27 .101 1 .00 22 .11 C

ATOM 1419 O ARG A1164 -38 .138 36 .872 26 .728 1 .00 21, .86 O

ATOM 1420 CB ARG A1164 -37 .603 39 .125 28 .663 1 .00 19, .06 C

ATOM 1421 CG ARG A1164 -37 .195 38 .484 29 .979 1 .00 20, .78 C

ATOM 1422 CD ARG A1164 -38 .083 38 .940 31 .135 1 .00 24 .44 C

ATOM 1423 NE ARG A1164 -37 .981 40 .375 31 .398 1, .00 23, .39 N

ATOM 1424 CZ ARG A1164 -37 .051 40 .941 32 .165 1 .00 27 .47 C

ATOM 1425 NHl ARG A1164 -36, .120 40, .204 32 .763 1 .00 28, .03 N

ATOM 1426 NH2 ARG A1164 -37 .039 42 .257 32 .317 1 .00 28, .25 N

ATOM 1427 N LYS A1165 -35, .977 36, .407 27 .190 1 .00 23, .31 N

ATOM 1428 CA LYS A1165 -36 .094 34 .997 26 .839 1 .00 28, .12 C

ATOM 1429 C LYS A1165 -36, .986 34, .230 27 .803 1, .00 31, ,03 C

ATOM 1430 O LYS A1165 -36 .864 34 .362 29 .024 1 .00 31, .25 O

ATOM 1431 CB LYS All6-5 -34, .712 34, .348 26 .754 1, .00 29. .41 c

ATOM 1432 CG LYS A1165 -34, .748 32 .845 26 .541 1, .00 31, .44 c

ATOM 1433 CD LYS A1165 -33, .404 32, .302 26, .076 1, .00 32. .68 c

ATOM 1434 CE LYS A1165 -33, .308 30, .811 26 .335 1, .00 31. .76 c

ATOM 1435 NZ LYS A1165 -32, .994 30, .552 27, .774 1, .00 30. .44 N

ATOM 1436 N GLY A1166 -37, .881 33, .423 27 .237 1, .00 32. .51 N

ATOM 1437 CA GLY A1166 -38. .800 32, .637 28, .043 1. .00 34. .80 C

ATOM 1438 C GLY A1166 -38, ,199 31, .397 28, .686 1, .00 35. .11 C

ATOM 1439 O GLY A1166 -37. .629 31. .461 29. .779 1. ,00 36. .85 O

ATOM 1440 N GLY A1167 -38, ,312 30, .263 28, .002 1, .00 34. .50 N

ATOM 1441 CA GLY A1167 -37. .796 29. .018 28, .550 1. .00 35. .03 C

ATOM 1442 C GLY A1167 -36, .300 28, .801 28, .436 1. ,00 33. .78 c

ATOM 1443 O GLY A1167 -35. .498 29. .717 28, .639 1. .00 33. .70 0

ATOM 1444 N LYS A1168 -35, .936 27, .551 28, .174 1. .00 31. .70 N

ATOM 1445 CA LYS A1168 -34. .549 27. .151 28. .014 1. .00 30. ,10 C

ATOM 1446 C LYS A1168 -34. .254 27. .023 26, .526 1. .00 28. ,77 C

ATOM 1447 O LYS A1168 -35. .149 26. .729 25. .728 1. .00 25. ,16 O

ATOM 1448 CB LYS A1168 -34. .293 25. .812 28, .717 1. .00 30. .15 C

ATOM 1449 N GLY A1169 -32. .995 27. .253 26. .165 1. ,00 26. ,18 N

ATOM 1450 CA GLY A1169 -32. ,586 27. .164 24. .777 1. .00 24. .56 C

ATOM 1451 C GLY A1169 -31. ,087 27. .316 24. .637 1. .00 22. ,84 C

ATOM 1452 O GLY A1169 -30. .403 27. .666 25. .606 1. .00 22. ,26 0

ATOM 1453 N LEU A1170 -30. .587 27. .067 23. .427 1. ,00 21. ,50 N

ATOM 1454 CA LEU A1170 -29. .157 27. .157 23. ,134 1. .00 21. ,86 C

ATOM 1455 C LEU A1170 -28. .731 28. ,597 22. ,943 1. ,00 21. ,12 c

ATOM 1456 O LEU A1170 -29. .178 29. .272 22. .009 1. .00 20. ,59 0

ATOM 1457 CB LEU A1170 -28. ,810 26. .341 21. ,888 1, ,00 22. .48 c

ATOM 1458 CG LEU A1170 -28. .897 24. ,821 22. .058 1. ,00 24. ,52 c

ATOM 1459 CDl LEU A1170 -28. ,674 24. .138 20. ,717 1, ,00 22. ,77 c

ATOM 1460 CD2 LEU A1170 -27. .866 24. .363 23. .074 1, .00 21. ,97 c

ATOM 1461 N LEU A1171 -27. .861 29. .059 23. ,837 1. 00 20. 27 N

si ATOM 1462 CA LEU A1171 -27.372 30.432 23.809 1.00 17.88 C

ATOM 1463 C LEU A1171 -25 .860 30 .494 23 .591 1 .00 14 .10 c

ATOM 1464 O LEU A1171 -25 .120 29 .693 24 .141 1 .00 14 .94 0

ATOM 1465 CB LEU A1171 -27 .735 31 .132 25 .123 1 .00 16 .85 c

ATOM 1466 CG LEU A1171 -29 .231 31 .197 25 .435 1 .00 19 .02 c

ATOM 1467 CDl LEU A1171 -29 .448 31 .872 26 .777 1 .00 22 .19 c

ATOM 1468 CD2 LEU A1171 -29 .950 31 .950 24 .336 1 .00 18 .99 c

ATOM 1469 N PRO A1172 -25 .396 31 .443 22 .761 1 .00 14 .82 N

ATOM 1470 CA PRO A1172 -23 .968 31 .619 22 .462 1 .00 13 .38 C

ATOM 1471 C PRO A1172 -23 .261 32 .339 23 .615 1 .00 11 .66 C

ATOM 1472 O PRO A1172 -22 .876 33 .497 23 .490 1 .00 11 .29 O

ATOM 1473 CB PRO A1172 -24 .000 32 .469 21 .191 1. .00 11 .41 c

ATOM 1474 CG PRO A1172 -25 .207 33 .346 21 .411 1 .00 15 .12 c

ATOM 1475 CD PRO A1172 -26 .227 32 .377 21 .970 1 .00 12 .97 c

ATOM 1476 N VAL A1173 -23 .095 31 .633 24 .734 1 .00 12 .14 N

ATOM 1477 CA VAL A1173 -22 .484 32 .175 25 .948 1 .00 13 .99 C

ATOM 1478 C VAL A1173 -21 .256 33 .084 25 .791 1 .00 13 .22 C

ATOM 1479 O VAL A1173 -21 .201 34 .154 26 .402 1. .00 13 .44 O

ATOM 1480 CB VAL A1173 -22, .170 31 .029 26, .962 1, .00 16 .35 C

ATOM 1481 CGI VAL A1173 -21 .353 31 .554 28 .143 1 .00 15 .22 C

ATOM 1482 CG2 VAL A1173 -23 .480 30 .426 27 .475 1. .00 16 .47 C

ATOM 1483 N ARG A1174 -20, .286 32 .664 24 .979 1 .00 12 .70 N

ATOM 1484 CA ARG A1174 -19 .050 33 .435 24 .766 1 .00 12 .54 C

ATOM 1485 C ARG A1174 -19, .230 34 .777 24 .039 1, .00 12 .19 C

ATOM 1486 O ARG A1174 -18, .326 35 .611 24 .033 1 .00 10 .81 O

ATOM 1487 CB ARG A1174 -18, .003 32, .564 24, .063 1, .00 11 .05 C

ATOM 1488 CG ARG A1174 -17, .598 31, .333 24, .899 1. .00 12 .54 C

ATOM 1489 CD ARG A1174 -16. ,809 30, .314 24, .098 1, .00 14 .24 C

ATOM 1490 NE ARG A1174 -16. ,802 29, .028 24, .797 1, .00 16 .67 N

ATOM 1491 CZ ARG A1174 -15, .862 28, .631 25, .648 1, .00 17 .95 C

ATOM 1492 NHl ARG A1174 -14. .814 29, .403 25, .905 1. ,00 15 .98 N

ATOM 1493 NH2 ARG A1174 -16. .034 27, .507 26, ,336 1, .00 18 .08 N

ATOM 1494 N TRP A1175 -20. ,401 34. .982 23. .436 1. .00 11, .93 N

ATOM 1495 CA TRP A1175 -20. .695 36. .225 22, .728 1. .00 10 .52 C

ATOM 1496 C TRP A1175 -21. .711 37. .095 23. .457 1, .00 11, ,35 C

ATOM 1497 O TRP A1175 -22. ,005 38. .205 23. .018 1. .00 13, .36 O

ATOM 1498 CB TRP A1175 -21. .215 35, .920 21. .310 1. .00 8, .26 C

ATOM 1499 CG TRP A1175 -20. ,147 35. .435 20. .384 1. ,00 11, .30 C

ATOM 1500 CDl TRP A1175 -19. .458 36. ,182 19. .474 1. .00 8, .99 C

ATOM 1501 CD2 TRP A1175 -19. ,569 34. .118 20. ,343 1. ,00 9, .82 c

ATOM 1502 NEl TRP A1175 -18. ,481 35. ,424 18. .885 1. ,00 10. .26 N

ATOM 1503 CE2 TRP A1175 -18. ,520 34. ,154 19. ,401 1. ,00 9. .64 c

ATOM 1504 CE3 TRP A1175 -19. ,833 32. .914 21. .023 1. ,00 9. ,48 C

ATOM 1505 CZ2 TRP A1175 -17. .722 33. .038 19. .115 1. .00 10, .81 C

ATOM 1506 CZ3 TRP A1175 -19. ,040 31. ,801 20. .740 1. ,00 11. .88 c

ATOM 1507 CH2 TRP A1175 -17. ,994 31. .875 19. .794 1. ,00 12, .02 c

ATOM 1508 N MET A1176 -22. ,235 36. ,598 24. ,575 1. ,00 13. .35 N

ATOM 1509 CA MET A1176 -23. ,268 37. ,308 25. ,332 1. ,00 12. .01 c

ATOM 1510 C MET A1176 -22. 896 38. ,348 26. ,387 1. ,00 11. ,49 c

ATOM 1511 O MET A1176 -21. ,911 38. ,212 27. ,102 1. ,00 11. .92 O

ATOM 1512 CB MET A1176 -24. 226 36. ,293 25. ,956 1. 00 11. ,79 c

ATOM 1513 CG MET A1176 -25. 128 35. ,585 24. ,943 1. 00 13. .38 c

ATOM 1514 SD MET A1176 -25. ,895 34. ,108 25. ,640 1. ,00 15. .64 s

ATOM 1515 CE MET A1176 -26. 979 34. ,823 26. ,869 1. 00 15. ,85 c

ATOM 1516 N ALA A1177 -23. 719 39. ,391 26. ,479 1. ,00 9. .50 N

ATOM 1517 CA ALA A1177 -23. 530 40. 460 27. ,465 1. 00 9. ,30 c

ATOM 1518 C ALA A1177 -23. 878 39. ,931 28. ,861 1. 00 10. ,02 c

ri ATOM 1519 O ALA A1177 -24.717 39.041 28.998 1.00 12.36 O

ATOM 1520 CB ALA A1177 -24 .437 41 .632 27 .126 1 .00 10 .23 C

ATOM 1521 N PRO A1178 -23 .256 40 .490 29 .918 1, .00 8 .73 N

ATOM 1522 CA PRO A1178 -23 .544 40 .035 31 .287 1 .00 11 .26 C

ATOM 1523 C PRO A1178 -25 .027 40 .071 31 .694 1 .00 13 .66 C

ATOM 1524 O PRO A1178 -25 .508 39 .153 32 .361 1. .00 14 .69 0

ATOM 1525 CB PRO A1178 -22 .678 40 .956 32 .151 1 .00 10 .74 c

ATOM 1526 CG PRO A1178 -22 .370 42 .142 31 .253 1 .00 10 .11 c

ATOM 1527 CD PRO A1178 -22 .193 41 .508 29 .911 1 .00 8 .89 c

ATOM 1528 N GLU A1179 -25 .754 41 .109 31 .284 1 .00 13 .47 N

ATOM 1529 CA GLU A1179 -27 .180 41 .214 31 .626 1 .00 14 .59 C

ATOM 1530 C GLU A1179 -28 .056 40 .172 30 .924 1 .00 13 .80 C

ATOM 1531 O GLU A1179 -29 .121 39 .815 31 .428 1 .00 14 .49 0

ATOM 1532 CB GLU A1179 -27 .726 42 .633 31 .382 1 .00 14 .38 C

ATOM 1533 CG GLU A1179 -27 .886 43 .046 29 .921 1 .00 13 .77 C

ATOM 1534 CD GLU A1179 -26 .606 43 .577 29 .279 1 .00 12 .44 c

ATOM 1535 OEl GLU A1179 -25 .558 43 .649 29 .953 1, .00 11 .11 0

ATOM 1536 OΞ2 GLU A1179 -26 .655 43 .933 28 .084 1 .00 11 .55 0

ATOM 1537 N SER A1180 -27 .609 39 .688 29 .767 1, .00 12 .88 N

ATOM 1538 CA SER A1180 -28 .339 38 .667 29 .019 1, .00 14 .09 c

ATOM 1539 C SER A1180 -28 .089 37 .321 29 .673 1 .00 14 .70 C

ATOM 1540 O SER A1180 -28 .992 36 .492 29 .766 1, .00 15 .13 O

ATOM 1541 CB SER A1180 -27 .871 38 .598 27 .564 1, .00 13 .06 C

ATOM 1542 OG SER A1180 -28, .109 39, .816 26 .878 1, .00 14, .75 0

ATOM 1543 N LEU A1181 -26 .849 37 .109 30 .113 1, .00 16, .35 N

ATOM 1544 CA LEU A1181 -26, .472 35, .875 30, .793 1. .00 16, .56 c

ATOM 1545 C LEU A1181 -27 .176 35 .797 32 .152 1, .00 17 .63 c

ATOM 1546 O LEU A1181 -27 .526 34 .715 32 .624 1, .00 14 .76 O

ATOM 1547 CB LEU A1181 -24, .955 35, .827 31, .005 1, .00 15, .62 c

ATOM 1548 CG LEU A1181 -24 .063 35 .610 29 .782 1, .00 16 .39 c

ATOM 1549 CDl LEU A1181 -22. .618 35, .950 30, .144 1, .00 17, .17 c

ATOM 1550 CD2 LEU A1181 -24, .182 34, .166 29, .270 1, .00 13, .64 c

ATOM 1551 N LYS A1182 -27, ,384 36, .956 32, ,766 1. .00 18, ,10 N

ATOM 1552 CA LYS A1182 -28, .023 37, .027 34, .066 1. .00 18, .85 c

ATOM 1553 C LYS A1182 -29, .554 37, ,011 34, .041 1. ,00 21, .86 c

ATOM 1554 O LYS A1182 -30, .177 36, ,208 34, ,730 1. .00 21, .58 0

ATOM 1555 CB LYS A1182 -27, .535 38, .266 34, .818 1. .00 20, .48 c

ATOM 1556 CG LYS A1182 -28, .213 38, .467 36. .156 1. .00 21, .26 c

ATOM 1557 CD LYS A1182 -27, .665 39, .667 36, .890 1. .00 27, .78 c

ATOM 1558 CE LYS A1182 -28, .597 40, .059 38, .020 1. ,00 32, .84 c

ATOM 1559 NZ LYS A1182 -27, .944 40, .991 38, .979 1. ,00 39. .04 N

ATOM 1560 N ASP A1183 -30. .154 37. .894 33. .250 1. ,00 22. .37 N

ATOM 1561 CA ASP A1183 -31, .609 38, .001 33, .196 1. ,00 23. .81 c

ATOM 1562 C ASP A1183 -32, .259 37, .533 31, ,902 1. .00 22. .14 C

ATOM 1563 O ASP A1183 -33, .485 37. .497 31, .805 1. .00 21. .70 O

ATOM 1564 CB ASP A1183 -32, .034 39, ,449 33, .466 1. ,00 25. .54 C

ATOM 1565 CG ASP A1183 -31, .331 40. ,056 34. .671 1. ,00 29. .17 C

ATOM 1566 ODl ASP A1183 -31, ,339 39, .429 35, .747 1. ,00 28. .49 O

ATOM 1567 OD2 ASP A1183 -30. .764 41. .162 34. .535 1. ,00 34. .30 O

ATOM 1568 N GLY A1184 -31, .449 37, .182 30. .910 1. ,00 20. .46 N

ATOM 1569 CA GLY A1184 -31, .992 36, .745 29, .634 1. ,00 19. .84 C

ATOM 1570 C GLY A1184 -32, .580 37. .892 28, .829 1. ,00 19. .25 C

ATOM 1571 O GLY A1184 -33, .441 37, .683 27, .964 1. .00 18. .58 O

ATOM 1572 N VAL A1185 -32. .106 39. .106 29. .101 1. ,00 17. ,73 N

ATOM 1573 CA VAL A1185 -32, .587 40. .292 28. .405 1. ,00 17. .58 C

ATOM 1574 C VAL A1185 -31. .671 40. .695 27. .249 1. ,00 16. ,77 C

ATOM 1575 O VAL A1185 -30. .481 40. .947 27. ,446 1. ,00 16. ,98 O

<£?o ATOM 1576 CB VAL A1185 -32.750 41.469 29.373 1.00 17.28 C

ATOM 1577 CGI VAL A1185 -33 .292 42 .682 28 .632 1 .00 21 .67 C

ATOM 1578 CG2 VAL A1185 -33 .700 41 .080 30 .491 1 .00 18 .64 C

ATOM 1579 N PHE A1186 -32 .240 40 .747 26 .046 1 .00 14 .68 N

ATOM 1580 CA PHE A1186 -31 .498 41 .108 24 .842 1 .00 12 .75 C

ATOM 1581 C PHE A1186 -31 .992 42 .439 24 .275 1, .00 14 .16 C

ATOM 1582 O PHE A1186 -33 .195 42 .657 24 .108 1 .00 14 .12 O

ATOM 1583 CB PHE A1186 -31 .621 40 .013 23 .774 1 .00 11 .35 C

ATOM 1584 CG PHE A1186 -31 .076 38 .684 24 .204 1 .00 11 .68 C

ATOM 1585 CDl PHE A1186 -31 .799 37 .871 25, .068 1. .00 14 .51 C

ATOM 1586 CD2 PHE A1186 -29 .837 38 .247 23 .751 1 .00 15 .14 C

ATOM 1587 CE1 PHE A1186 -31 .295 36 .644 25 .484 1 .00 14 .59 C

ATOM 1588 CE2 PHE A1186 -29, .321 37 .019 24 .157 1 .00 14 .88 C

ATOM 1589 CZ PHE A1186 -30 .052 36 .215 25 .026 1 .00 15 .38 C

ATOM 1590 N THR A1187 -31 .040 43 .319 23 .985 1, .00 12 .37 N

ATOM 1591 CA THR A1187 -31 .309 44 .648 23 .449 1 .00 12 .43 C

ATOM 1592 C THR A1187 -30, .244 44 .941 22 .398 1, .00 12 .08 c

ATOM 1593 O THR A1187 -29 .330 44 .145 22 .183 1 .00 11 .81 0

ATOM 1594 CB THR A1187 -31, .116 45 .721 24, .540 1, .00 12, .13 c

ATOM 1595 OG1 THR A1187 -29 .745 45 .711 24 .954 1, .00 13 .13 0

ATOM 1596 CG2 THR A1187 -31, .989 45 .436 25, .750 1, .00 10, .25 c

ATOM 1597 N THR A1188 -30 .354 46 .091 21, .748 1. ,00 11 .60 N

ATOM 1598 CA THR A1188 -29, .347 46 .464 20, .769 1, .00 12, .44 c

ATOM 1599 C THR A1188 -28 .000 46 .630 21, .503 1, .00 11, .54 c

ATOM 1600 O THR A1188 -26, .934 46 .493 20, ,899 1. .00 9, .99 0

ATOM 1601 CB THR A1188 -29, .727 47 .758 20, .042 1, .00 14, .88 c

ATOM 1602 OG1 THR A1188 -28, .745 48 .034 19. .032 1, .00 18, .99 0

ATOM 1603 CG2 THR A1188 -29 .839 48 .936 21, .020 1, .00 15, .01 c

ATOM 1604 N SER A1189 -28, .062 46, .914 22. .808 1. .00 10, .39 N

ATOM 1605 CA SER A1189 -26, .854 47 .067 23, .631 1, .00 11, .73 C

ATOM 1606 C SER A1189 -26, ,151 45, .725 23. .810 1. .00 10. .66 c

ATOM 1607 O SER A1189 -24, .922 45 .668 23, .842 1, .00 10, .25 0

ATOM 1608 CB SER A1189 -27, .205 47, .627 25. .013 1. .00 14, .05 c

ATOM 1609 OG SER A1189 -27, .880 48, .860 24, .891 1. .00 24, ,15 0

ATOM 1610 N SER A1190 -26, ,924 44, .648 23. .939 1. .00 8. .99 N

ATOM 1611 CA SER A1190 -26, .321 43 .328 24, .081 1. .00 7, .03 C

ATOM 1612 C SER A1190 -25, .743 42, .892 22, ,724 1. ,00 7. .53 C

ATOM 1613 O SER A1190 -24, .783 42, .117 22. .677 1. .00 10, .69 0

ATOM 1614 CB SER A1190 -27, .303 42, .311 24, .702 1, .00 6, .46 c

ATOM 1615 OG SER A1190 -28, .475 42, .149 23. .935 1. .00 9. .64 0

ATOM 1616 N ASP A1191 -26, .314 43 .394 21, .621 1. .00 7, .48 N

ATOM 1617 CA ASP A1191 -25, .779 43, .103 20. .285 1. .00 8. .83 C

ATOM 1618 C ASP A1191 -24, .419 43, .818 20, .159 1. .00 9, .63 C

ATOM 1619 O ASP A1191 -23. .496 43, .300 19. .520 1, ,00 8. .57 O

ATOM 1620 CB ASP A1191 -26, .700 43, .615 19. .171 1. .00 7, .77 C

ATOM 1621 CG ASP A1191 -27. .806 42, .615 18. .776 1. .00 9. .58 C

ATOM 1622 OD1 ASP A1191 -27, .826 41, .444 19. .232 1. .00 9. ,51 0

ATOM 1623 OD2 ASP A1191 -28. .667 43, ,014 17. .978 1. .00 7. .86 0

ATOM 1624 N MET A1192 -24, .307 45, .007 20. .761 1. .00 7. .99 N

ATOM 1625 CA MET A1192 -23. .057 45, .777 20. .747 1. ,00 8. .69 C

ATOM 1626 C MET A1192 -21, .964 45, ,007 21. .496 1. .00 8. .95 c

ATOM 1627 O MET A1192 -20, .805 45, .027 21. .092 1. .00 10. ,93 0

ATOM 1628 CB MET A1192 -23, ,249 47, .160 21. .388 1. .00 8. .92 c

ATOM 1629 CG MET A1192 -22. .028 48. .083 21. .282 1. ,00 7. .83 c

ATOM 1630 SD MET A1192 -21, .387 48, .273 19. .601 1. .00 9. .72 s

ATOM 1631 CE MET A1192 -22. .714 49. .143 18. .782 1. ,00 6. ,76 c

ATOM 1632 N TRP A1193 -22. .336 44, .339 22. .586 1. ,00 8. .68 N

w ATOM 1633 CA TRP A1193 -21.377 43.533 23.337 1.00 9.34 C

ATOM 1634 C TRP A1193 -20 .829 42 .458 22 .399 1 .00 9 .96 C

ATOM 1635 O TRP A1193 -19 .622 42 .237 22 .357 1 .00 10 .79 O

ATOM 1636 CB TRP A1193 -22 .022 42 .866 24 .562 1 .00 7 .67 C

ATOM 1637 CG TRP A1193 -21 .070 41 .963 25 .312 1 .00 10 .10 C

ATOM 1638 CDl TRP A1193 -20 .652 40 .709 24 .937 1, .00 10 .77 C

ATOM 1639 CD2 TRP A1193 -20 .361 42 .272 26 .519 1 .00 11 .85 C

ATOM 1640 NΞl TRP A1193 -19 .722 40 .234 25 .825 1 .00 11 .88 N

ATOM 1641 CE2 TRP A1193 -19 .525 41 .168 26 .804 1 .00 12 .55 C

ATOM 1642 CΞ3 TRP A1193 -20 .348 43 .377 27 .380 1. .00 11 .50 C

ATOM 1643 CZ2 TRP A1193 -18 .684 41 .137 27 .926 1 .00 12 .37 C

ATOM 1644 CZ3 TRP A1193 -19 .512 43 .342 28 .493 1 .00 11 .99 C

ATOM 1645 CH2 TRP A1193 -18 .691 42 .226 28 .752 1 .00 11 .27 C

ATOM 1646 N SER A1194 -21 .723 41 .806 21 .651 1 .00 8 .60 N

ATOM 1647 CA SER A1194 -21 .339 40 .757 20 .693 1, .00 9 .71 C

ATOM 1648 C SER A1194 -20, .446 41 .322 19 .590 1, .00 9 .74 C

ATOM 1649 O SER A1194 -19, .490 40. .671 19 .153 1, .00 10 .32 O

ATOM 1650 CB SER A1194 -22 .586 40 .113 20 .073 1, .00 7 .94 C

ATOM 1651 OG SER A1194 -23, .408 39, .536 21 .073 1, .00 11 .28 O

ATOM 1652 N PHE A1195 -20 .754 42 .541 19 .146 1, .00 9 .20 N

ATOM 1653 CA PHE A1195 -19, .968 43, .207 18 .108 1, .00 7 .37 C

ATOM 1654 C PHE A1195 -18, .516 43 .332 18 .579 1, .00 7 .39 C

ATOM 1655 O PHE A1195 -17, .580 43, .174 17, .793 1, ,00 7, .91 O

ATOM 1656 CB PHE A1195 -20, .542 44, .597 17 .820 1, ,00 7 .12 C

ATOM 1657 CG PHE A1195 -19, .727 45, .400 16, .841 1. .00 6, .80 C

ATOM 1658 CDl PHE A1195 -19, .756 45, .096 15 .478 1, .00 9 .68 C

ATOM 1659 CD2 PHE A1195 -18, .955 46, .477 17, .273 1. .00 8, .08 C

ATOM 1660 CEl PHE A1195 -19, .035 45, .853 14 .562 1, .00 9, .12 C

ATOM 1661 CE2 PHE A1195 -18. .227 47, .244 16, .359 1. .00 4, .84 C

ATOM 1662 CZ PHE A1195 -18, ,264 46, .938 15, .009 1. .00 6 .13 c

ATOM 1663 N GLY A1196 -18. .342 43, .622 19, ,864 1. .00 7, .81 N

ATOM 1664 CA GLY A1196 -17, .006 43, .725 20, .433 1. .00 7, .51 c

ATOM 1665 C GLY A1196 -16. .263 42, .400 20, .335 1. .00 9, .25 c

ATOM 1666 O GLY A1196 -15. .066 42, ,365 20, .032 1. .00 9, .58 0

ATOM 1667 N VAL A1197 -16. .974 41. .299 20, .576 1. .00 9, ,03 N

ATOM 1668 CA VAL A1197 -16. .361 39, .978 20, .489 1. .00 10, .09 C

ATOM 1669 C VAL A1197 -15. .980 39, .696 19. .042 1. .00 10, .21 C

ATOM 1670 O VAL A1197 -14. .952 39, ,079 18, ,787 1. .00 10, .95 O

ATOM 1671 CB VAL A1197 -17. .291 38. ,859 21. .032 1. ,00 12. .12 C

ATOM 1672 CGI VAL A1197 -16. .558 37. ,507 21. .001 1. ,00 11, .66 c

ATOM 1673 CG2 VAL A1197 -17. .714 39. .177 22. .472 1. ,00 11. .35 c

ATOM 1674 N VAL A1198 -16. .802 40. ,151 18. .094 1. .00 7. .98 N

ATOM 1675 CA VAL A1198 -16. .499 39. .960 16. .674 1. ,00 7. .70 C

ATOM 1676 C VAL A1198 -15. .191 40. .682 16. .324 1. ,00 8. .01 C

ATOM 1677 O VAL A1198 -14. .377 40. .169 15. .565 1. ,00 6. ,63 O

ATOM 1678 CB VAL A1198 -17. .642 40. .469 15. .768 1. ,00 8. .32 C

ATOM 1679 CGI VAL A1198 -17. ,228 40. .381 14. .288 1. 00 9. .03 C

ATOM 1680 CG2 VAL A1198 -18, .910 39. ,643 16. .020 1. ,00 9. .72 C

ATOM 1681 N LEU A1199 -14. ,996 41. .876 16. .883 1. ,00 7. ,71 N

ATOM 1682 CA LEU A1199 -13. .765 42. .630 16. .645 1. ,00 7. .97 C

ATOM 1683 C LEU A1199 -12. .592 41. ,830 17. ,226 1. ,00 8. ,28 C

ATOM 1684 O LEU A1199 -11. .491 41. ,826 16. .674 1. ,00 8. .69 O

ATOM 1685 CB LEU A1199 -13. .843 44. ,003 17. .319 1. ,00 9. ,02 C

ATOM 1686 CG LEU A1199 -14. .949 44. .968 16. .878 1. ,00 4, .98 C

ATOM 1687 CDl LEU A1199 -14. .868 46. .218 17. .748 1. ,00 10. ,63 C

ATOM 1688 CD2 LEU A1199 -14. .781 45. .319 15. .403 1. ,00 8. .51 C

ATOM 1689 N TRP A1200 -12. ,842 41. ,148 18. .339 1. ,00 9. ,31 N

b^ ATOM 1690 CA TRP A1200 -11.823 40.322 18.986 1.00 10.99 c

ATOM 1691 C TRP A1200 -11 .486 39 .142 18 .068 1 .00 11 .34 c

ATOM 1692 O TRP A1200 -10 .318 38 .774 17 .920 1 .00 11 .69 o

ATOM 1693 CB TRP A1200 -12 .319 39 .845 20 .360 1 .00 10 .73 c

ATOM 1694 CG TRP A1200 -11 .319 39 .045 21 .128 1 .00 12 .27 c

ATOM 1695 CDl TRP A1200 10 .444 39 .510 22 .073 1 .00 12 .33 c

ATOM 1696 CD2 TRP A1200 -11 .075 37 .635 21 .010 1 .00 12 .98 c

ATOM 1697 NΞl TRP A1200 -9 .670 38 .475 22 .544 1 .00 13 .01 N

ATOM 1698 CE2 TRP A1200 10 .035 37 .313 21 .908 1 .00 14 .85 C

ATOM 1699 CE3 TRP A1200 11 .633 36 .610 20 .226 1 .00 12 .28 C

ATOM 1700 CZ2 TRP A1200 -9 .539 36 .009 22 .047 1 .00 16 .76 c

ATOM 1701 CZ3 TRP A1200 11 .139 35 .316 20 .364 1 .00 15 .01 c

ATOM 1702 CH2 TRP A1200 10 .102 35 .031 21 .268 1 .00 14 .91 c

ATOM 1703 N GLU A1201 12 .505 38 .552 17 .441 1 .00 11 .17 N

ATOM 1704 CA GLU A1201 12 .286 37 .440 16 .520 1 .00 9 .10 C

ATOM 1705 C GLU A1201 11 .511 37 .919 15 297 1 00 9 .80 C

ATOM 1706 O GLU A1201 10 .616 37 .231 14 .819 1 00 10 .69 O

ATOM 1707 CB GLU A1201 13 .615 36 .823 16 .077 1 .00 10 .68 C

ATOM 1708 CG GLU A1201 14 387 36 .166 17 198 1 00 8 00 c

ATOM 1709 CD GLU A1201 15 691 35 .569 16 721 1 00 12 76 c

ATOM 1710 OEl GLU A1201 16 710 36 .292 16 722 1 00 9 .80 o

ATOM 1711 OE2 GLU A1201 15 687 34 383 16 324 1 00 8 95 o

ATOM 1712 N ILE A1202 11 848 39 .104 14 790 1 00 9 01 N

ATOM 1713 CA ILE A1202 11 140 39 .652 13 631 1 00 7 60 C

ATOM 1714 C ILE A1202 -9 .655 39 .884 13 957 1 00 9 83 C

ATOM 1715 O ILE A1202 -8 772 39 508 13 175 1 00 10 02 O

ATOM 1716 CB ILE A1202 11 778 40 996 13 138 1 00 7 13 C

ATOM 1717 CGI ILE A1202 13 187 40 732 12 565 1 00 7 31 c

ATOM 1718 CG2 ILE A1202 10 918 41 628 12 038 1 00 8 23 c

ATOM 1719 CDl ILE A1202 13 958 42 010 12 237 1 00 11 47 c

ATOM 1720 N THR A1203 -9 380 40 494 15 108 1 00 11 25 N

ATOM 1721 CA THR A1203 -7 999 40 768 15 505 1 00 12 71 C

ATOM 1722 C THR A1203 -7 199 39 554 16 020 1 00 15 29 C

ATOM 1723 O THR A1203 -5 994 39 657 16 263 1 00 14 51 O

ATOM 1724 CB THR A1203 -7 924 41 936 16 505 1 00 10 76 c

ATOM 1725 OG1 THR A1203 -8 769 41 667 17 629 1 00 14 82 o

ATOM 1726 CG2 THR A1203 -8 350 43 238 15 834 1 00 12 72 c

ATOM 1727 N SER A1204 -7 859 38 409 16 188 1 00 12 81 N

ATOM 1728 CA SER A1204 -7 167 37 193 16 626 1 00 12 43 C

ATOM 1729 C SER A1204 -7 228 36 130 15 531 1 00 13 21 C

ATOM 1730 O SER A1204 -6 781 34 998 15 728 1 00 14 36 O

ATOM 1731 CB SER A1204 -7 785 36 639 17 917 1 00 15 36 C

ATOM 1732 OG SER A1204 -9 089 36 131 17 686 1 00 16 96 O

ATOM 1733 N LEU A1205 -7 772 36 501 14 371 1 00 12 73 N

ATOM 1734 CA LEU A1205 -7 941 35 577 13 245 1 00 14 23 C

ATOM 1735 C LEU A1205 -8 792 34 368 13 647 1 00 14 72 C

ATOM 1736 O LEU A1205 -8 463 33 212 13 374 1. 00 13 29 O

ATOM 1737 CB LEU A1205 -6 599 35 139 12 644 1 00 11 22 C

ATOM 1738 CG LEU A1205 -5 792 36 221 11 929 1 00 14 09 C

ATOM 1739 CDl LEU A1205 -4 638 35 561 11 189 1 00 17 23 C

ATOM 1740 CD2 LEU A1205 -6 671 36 967 10 945 1 00 12 05 C

ATOM 1741 N ALA A1206 -9 891 34 677 14 326 1 00 14 80 N

ATOM 1742 CA ALA A1206 10 869 33 706 14 788 1 00 15 72 C

ATOM 1743 C ALA A1206 10 437 32 619 15 767 1. 00 15 85 C

ATOM 1744 O ALA A1206 10 721 31 434 15 570 1. 00 12 20 O

ATOM 1745 CB ALA A1206 11 610 33 098 13 601 1 00 14 84 C

ATOM 1746 N GLU A1207 -9 745 33 014 16. 826 1. 00 16 12 N ATOM 1747 CA GLU A1207 -9.387 32.041 17.844 1.00 17.71 C

ATOM 1748 C GLU A1207 -10 .650 31 .905 18 .686 1 .00 16 .08 C

ATOM 1749 O GLU A1207 -11 .593 32 .667 18 .508 1 .00 14 .74 0

ATOM 1750 CB GLU A1207 -8 .213 32 .535 18 .679 1 .00 18 .40 c

ATOM 1751 CG GLU A1207 -7 .003 32 .786 17 .818 1 .00 25 .81 c

ATOM 1752 CD GLU A1207 -5 .692 32 .536 18 .521 1 .00 31 .34 c

ATOM 1753 OEl GLU A1207 -5 .534 32 .943 19 .694 1 .00 36 .14 0

ATOM 1754 OE2 GLU A1207 -4 .810 31 .937 17 .874 1 .00 31 .59 0

ATOM 1755 N GLN A1208 -10 .681 30 .939 19 .593 1 .00 18 .66 N

ATOM 1756 CA GLN A1208 -11 .863 30 .741 20 .426 1 .00 18 .74 c

ATOM 1757 C GLN A1208 -11 .875 31 .664 21 .630 1 .00 17 .33 c

ATOM 1758 O GLN A1208 -10 .922 31 .687 22 .407 1, .00 15 .80 0

ATOM 1759 CB GLN A1208 -11, .952 29 .283 20 .897 1, .00 22 .09 c

ATOM 1760 CG GLN A1208 -13, .128 28 .969 21 .830 1 .00 23 .85 c

ATOM 1761 CD GLN A1208 -14, .494 28 .958 21 .141 1 .00 29 .76 c

ATOM 1762 OEl GLN A1208 -15 .472 28 .471 21 .710 1 .00 30 .07 0

ATOM 1763 NE2 GLN A1208 -14, .569 29 .488 19 .926 1, .00 34 .07 N

ATOM 1764 N PRO A1209 -12 .949 32 .466 21 .787 1, .00 16 .08 N

ATOM 1765 CA PRO A1209 -13, .023 33, .373 22 .935 1, .00 16 .01 C

ATOM 1766 C PRO A1209 -12 .976 32 .574 24 .234 1 .00 15 .22 C

ATOM 1767 O PRO A1209 -13, .628 31, .535 24 .351 1, .00 17 .66 O

ATOM 1768 CB PRO A1209 -14, .397 34. .031 22 .760 1, .00 18, .48 C

ATOM 1769 CG PRO A1209 -14, .609 34, .016 21 .275 1, .00 16 .02 C

ATOM 1770 CD PRO A1209 -14, .123 32, .636 20 .908 1, .00 16, .35 C

ATOM 1771 N TYR A1210 -12, .205 33 .064 25 .202 1, .00 15 .42 N

ATOM 1772 CA TYR A1210 -12, .067 32, .423 26 .511 1, .00 14, .05 C

ATOM 1773 C TYR A1210 -11, .582 30 .976 26 .413 1, .00 14 .39 C

ATOM 1774 O TYR A1210 -12, .029 30, .110 27 .168 1. .00 14, .42 O

ATOM 1775 CB TYR A1210 -13, .380 32 .468 27 .310 1, .00 13 .92 C

ATOM 1776 CG TYR A1210 -14. .088 33, .814 27 .325 1, .00 14, .67 C

ATOM 1777 CDl TYR A1210 -13, .801 34, .769 28, .299 1. ,00 13. .58 C

ATOM 1778 CD2 TYR A1210 -15, .045 34, .125 26 .357 1, .00 12, .13 C

ATOM 1779 CE1 TYR A1210 -14. .449 36, .013 28, .306 1, .00 13, .83 C

ATOM 1780 CE2 TYR A1210 -15. .696 35, .363 26 .353 1, .00 14, .20 C

ATOM 1781 CZ TYR A1210 -15. .391 36, .298 27, .327 1. .00 12. .66 c

ATOM 1782 OH TYR A1210 -16. .014 37, .520 27, .301 1, .00 13, .56 0

ATOM 1783 N GLN A1211 -10. .664 30, .725 25, ,483 1. .00 15. .31 N

ATOM 1784 CA GLN A1211 -10. .093 29, .396 25, .303 1, ,00 17, .34 c

ATOM 1785 C GLN A1211 -9. .506 28, .959 26, .646 1. ,00 15, .94 c

ATOM 1786 O GLN A1211 -8, ,701 29, .672 27, .247 1. .00 13, .92 0

ATOM 1787 CB GLN A1211 -9. .002 29, .431 24, .220 1. .00 17, .73 c

ATOM 1788 CG GLN A1211 -8. ,308 28. .095 23. .961 1. .00 23. .74 c

ATOM 1789 CD GLN A1211 -9. .276 26, .978 23, .624 1. .00 28, .14 c

ATOM 1790 OEl GLN A1211 -9. .573 26. .125 24, .462 1. .00 35. .54 0

ATOM 1791 NE2 GLN A1211 -9. .770 26, .972 22, .393 1. .00 33, .63 N

ATOM 1792 N GLY A1212 -9. .923 27. .791 27. ,115 1. .00 16. .53 N

ATOM 1793 CA GLY A1212 -9. .430 27, .299 28, .388 1. .00 18. .67 C

ATOM 1794 C GLY A1212 -10. .494 27, .291 29, .463 1. .00 19. .12 C

ATOM 1795 O GLY A1212 -10. .323 26, .652 30, .503 1. .00 18, .85 O

ATOM 1796 N LEU A1213 -11, .560 28, .060 29, .246 1. .00 17. .84 N

ATOM 1797 CA LEU A1213 -12. ,679 28. .104 30. .176 1, ,00 16. ,51 C

ATOM 1798 C LEU A1213 -13, .867 27. .406 29. .521 1. .00 17. .80 C

ATOM 1799 O LEU A1213 -14. ,049 27. .473 28. .305 1. .00 16. ,42 O

ATOM 1800 CB LEU A1213 -13. .067 29. .544 30, .521 1. .00 15. .22 C

ATOM 1801 CG LEU A1213 -12. ,063 30. .420 31. .275 1. .00 15. ,07 C

ATOM 1802 CDl LEU A1213 -12. .682 31, .779 31, .562 1. .00 14. .65 C

ATOM 1803 CD2 LEU A1213 -11. ,655 29. .738 32. .570 1. .00 15. ,49 C ATOM 1804 N SER A1214 -14.666 26.724 30.330 1.00 19.26 N

ATOM 1805 CA SER A1214 -15 .849 26 .040 29 .821 1 .00 20 .53 C

ATOM 1806 C SER A1214 -16 .944 27 .099 29 .727 1 .00 21 .29 C

ATOM 1807 O SER A1214 -16 .778 28 .202 30 .245 1 .00 19 .78 O

ATOM 1808 CB SER A1214 -16 .280 24 .945 30 .798 1 .00 16 .82 c

ATOM 1809 OG SER A1214 -16 .560 25 .506 32 .067 1 .00 19 .63 0

ATOM 1810 N ASN A1215 -18 .059 26 .764 29 .082 1 .00 21 .94 N

ATOM 1811 CA ASN A1215 -19 .175 27 .696 28 .946 1 .00 22 .09 c

ATOM 1812 C ASN A1215 -19 .690 28 .155 30 .301 1 .00 19 .81 c

ATOM 1813 O ASN A1215 -20 .064 29 .313 30 .471 1 .00 19 .19 O

ATOM 1814 CB ASN A1215 -20 .305 27 .073 28 .119 1 .00 22 .44 c

ATOM 1815 CG ASN A1215 -20 .022 27 .115 26 .629 1 .00 26 .25 c

ATOM 1816 OD1 ASN A1215 -19 .318 28 .006 26 .147 1 .00 29 .07 O

ATOM 1817 ND2 ASN A1215 -20 .566 26 .152 25 .887 1 .00 25 .59 N

ATOM 1818 N GLU A1216 -19 .701 27 .244 31 .268 1 .00 19 .63 N

ATOM 1819 CA GLU A1216 -20. .153 27 .563 32 .613 1, .00 20 .13 c

ATOM 1820 C GLU A1216 -19 .211 28 .545 33 .314 1 .00 18 .62 C

ATOM 1821 O GLU A1216 -19 .656 29 .434 34 .049 1. .00 19 .58 0

ATOM 1822 CB GLU A1216 -20 .290 26 .284 33 .434 1 .00 26 .29 C

ATOM 1823 CG GLU A1216 -21 .385 25 .368 32 .935 1 .00 30 .25 c

ATOM 1824 CD GLU A1216 -21 .565 24 .154 33 .817 1, .00 37 .50 c

ATOM 1825 OEl GLU A1216 -21 .889 24 .324 35 .014 1, .00 38 .29 O

ATOM 1826 OE2 GLU A1216 -21, .385 23 .026 33 .308 1, .00 42 .94 0

ATOM 1827 N GLN A1217 -17 .910 28 .383 33 .083 1, .00 18 .06 N

ATOM 1828 CA GLN A1217 -16 .902 29 .269 33 .672 1, .00 16 .96 c

ATOM 1829 C GLN A1217 -16, .975 30 .659 33 .043 1, .00 14 .49 C

ATOM 1830 O GLN A1217 -16 .814 31 .667 33 .727 1, .00 15 .17 O

ATOM 1831 CB GLN A1217 -15, .502 28, .682 33, .477 1. .00 18 .08 C

ATOM 1832 CG GLN A1217 -15, .208 27 .483 34, .377 1, .00 19 .21 C

ATOM 1833 CD GLN A1217 -13 .872 26 .846 34 .066 1, .00 19 .29 c

ATOM 1834 OEl GLN A1217 -13, .616 26, .455 32, .932 1. .00 20, .17 0

ATOM 1835 NE2 GLN A1217 -13, .004 ,26, .761 35, .062 1. .00 20, .44 N

ATOM 1836 N VAL A1218 -17, .217 '30, .696 31, .736 1. .00 14, .95 N

ATOM 1837 CA VAL A1218 -17, .342 31, .953 30, ,996 1. .00 13, .80 C

ATOM 1838 C VAL A1218 -18. .544 32, ,744 31, .517 1. .00 15, .67 C

ATOM 1839 O VAL A1218 -18, .441 33, .941 31. .772 1. .00 15, .00 O

ATOM 1840 CB VAL A1218 -17, .528 31, .687 29, .484 1. ,00 13, .87 C

ATOM 1841 CGI VAL A1218 -17. .808 32. .995 28. .731 1. .00 11, .77 C

ATOM 1842 CG2 VAL A1218 -16, .283 31, .006 28. .913 1. .00 11, .28 C

ATOM 1843 N LEU A1219 -19. .680 32. .058 31. .671 1. ,00 15. ,29 N

ATOM 1844 CA LEU A1219 -20. .922 32. .663 32. .164 1. .00 16. .71 C

ATOM 1845 C LEU A1219 -20. .667 33. .369 33. ,492 1. .00 16, .62 c

ATOM 1846 O LEU A1219 -21. .054 34. .528 33. .686 1. ,00 16. .96 O

ATOM 1847 CB LEU A1219 -21. ,996 31. .564 32. .320 1. .00 19, .20 c

ATOM 1848 CG LEU A1219 -23. .388 31. .795 32. .934 1. ,00 20. .32 c

ATOM 1849 CDl LEU A1219 -23. .357 31. .898 34. .450 1. ,00 20. .42 c

ATOM 1850 CD2 LEU A1219 -24. .002 33. .021 32. .348 1. .00 21, .52 c

ATOM 1851 N LYS A1220 -20. .008 32. .659 34. ,402 1. ,00 17. .78 N

ATOM 1852 CA LYS A1220 -19. ,676 33. .188 35. .718 1. ,00 18. .99 c

ATOM 1853 C LYS A1220 -18. .672 34. ,343 35. ,613 1. 00 17. .94 c

ATOM 1854 O LYS A1220 -18. .820 35. .372 36. .271 1. ,00 17. ,30 0

ATOM 1855 CB LYS A1220 -19. ,109 32. ,052 36. ,584 1. ,00 21. ,55 c

ATOM 1856 CG LYS A1220 -18. .490 32. .455 37. ,917 1. 00 26. ,84 c

ATOM 1857 CD LYS A1220 -19. .467 33. .158 38. .821 1. ,00 32. .26 c

ATOM 1858 CE LYS A1220 -18. ,920 33, ,236 40. ,236 1. ,00 35, ,10 c

ATOM 1859 NZ LYS A1220 -19. ,690 34. .222 41. ,047 1. ,00 38. .71 N

ATOM 1860 N PHE A1221 -17. ,653 34. ,162 34. ,779 1. 00 17, ,14 N

bύ ATOM 1861 CA PHE A1221 -16.619 35.181 34.594 1.00 17.76 C

ATOM 1862 C PHE A1221 -17 .179 36 .526 34 .137 1 .00 16 .90 C

ATOM 1863 O PHE A1221 -16 .909 37 .568 34 .751 1 .00 14 .75 O

ATOM 1864 CB PHE A1221 -15 .588 34 .695 33 .574 1 .00 16 .53 C

ATOM 1865 CG PHE A1221 -14 .467 35 .666 33 .329 1 .00 16 .51 C

ATOM 1866 CDl PHE A1221 -13 .729 36 .180 34 .391 1 .00 16 .31 C

ATOM 1867 CD2 PHE A1221 -14 .133 36 .043 32 .033 1 .00 16 .98 C

ATOM 1868 CEl PHE A1221 -12 .668 37 .053 34 .171 1 .00 14 .83 C

ATOM 1869 CE2 PHE A1221 -13 .074 36 .916 31 .794 1 .00 15 .98 C

ATOM 1870 CZ PHE A1221 -12 .337 37 .423 32 .867 1 .00 17 .03 C

ATOM 1871 N VAL A1222 -17 .955 36 .485 33 .055 1 .00 14 .64 N

ATOM 1872 CA VAL A1222 -18 .544 37 .687 32 .470 1 .00 15 .20 C

ATOM 1873 C VAL A1222 -19 .557 38 .351 33 .397 1 .00 16 .38 C

ATOM 1874 O VAL A1222 -19 .564 39 .574 33 .536 1 .00 17 .37 O

ATOM 1875 CB VAL A1222 -19 .168 37 .372 31 .099 1 .00 11 .50 C

ATOM 1876 CGI VAL A1222 -19 .825 38 .615 30 .494 1 .00 11 .96 C

ATOM 1877 CG2 VAL A1222 -18 .093 36 .853 30 .167 1 .00 13 .31 C

ATOM 1878 N MET A1223 -20 .411 37 .556 34 .033 1 .00 18 .24 N

ATOM 1879 CA MET A1223 -21 .389 38 .117 34 .960 1 .00 20 .52 C

ATOM 1880 C MET A1223 -20 .678 38 .825 36 .120 1 .00 21 .31 C

ATOM 1881 O MET A1223 -21 .175 39 .818 36 .652 1 .00 21 .35 0

ATOM 1882 CB MET A1223 -22 .343 37 .029 35 .468 1 .00 20 .64 c

ATOM 1883 CG MET A1223 -23, .453 36 .673 34 .479 1, .00 19, .71 c

ATOM 1884 SD MET A1223 -24 .594 35 .407 35 .108 1 .00 24 .12 s

ATOM 1885 CE MET A1223 -25 .148 36 .150 36 .629 1, .00 25, .07 c

ATOM 1886 N ASP A1224 -19 .505 38 .313 36 .492 1 .00 23 .17 N

ATOM 1887 CA ASP A1224 -18 .704 38 .904 37 .568 1, .00 22, .30 C

ATOM 1888 C ASP A1224 -17. .974 40, .170 37, .120 1, .00 21, .08 C

ATOM 1889 O ASP A1224 -17, .281 40 .798 37, .916 1, .00 20, .53 O

ATOM 1890 CB ASP A1224 -17, .670 37, .902 38, .091 1. .00 22, .27 C

ATOM 1891 CG ASP A1224 -18, .284 36 .797 38, .935 1, .00 27, .18 C

ATOM 1892 OD1 ASP A1224 -19, .469 36, .903 39, .326 1. .00 29. .68 0

ATOM 1893 OD2 ASP A1224 -17. .562 35, .814 39. .219 1. .00 28. .08 0

ATOM 1894 N GLY A1225 -18, .124 40, .535 35. .847 1. ,00 19. .18 N

ATOM 1895 CA GLY A1225 -17. .476 41. .730 35, .328 1. ,00 17. ,53 C

ATOM 1896 C GLY A1225 -16, .253 41, .477 34, .460 1. .00 17. .11 C

ATOM 1897 O GLY A1225 -15. .537 42. .410 34, .111 1. .00 17. ,08 O

ATOM 1898 N GLY A1226 -16. .017 40. .219 34. ,101 1. ,00 16. ,30 N

ATOM 1899 CA GLY A1226 -14. .873 39. .896 33. .276 1. .00 13. ,85 C

ATOM 1900 C GLY A1226 -15. ,116 40. .124 31. ,799 1. ,00 14. ,64 C

ATOM 1901 O GLY A1226 -16. .245 40. .341 31. .370 1. .00 14. ,50 O

ATOM 1902 N TYR A1227 -14. ,030 40. .132 31. ,035 1. ,00 16. ,76 N

ATOM 1903 CA TYR A1227 -14. ,066 40. ,312 29. ,586 1. ,00 16. 90 c

ATOM 1904 C TYR A1227 -12, .754 39. .793 29. .010 1. ,00 16. ,21 c

ATOM 1905 O TYR A1227 -11. ,819 39. ,472 29. .752 1. ,00 14. 31 O

ATOM 1906 CB TYR A1227 -14. .313 41. .783 29. ,197 1. ,00 19. ,48 c

ATOM 1907 CG TYR A1227 -13. ,406 42. ,784 29. ,883 1. ,00 21. 31 c

ATOM 1908 CDl TYR A1227 -12. 062 42. ,888 29. 537 1. 00 24. 44 c

ATOM 1909 CD2 TYR A1227 -13. ,883 43. ,585 30. ,918 1. ,00 25. 42 c

ATOM 1910 CEl TYR A1227 -11. 208 43. ,754 30. 212 1. 00 28. 84 c

ATOM 1911 CΞ2 TYR A1227 -13. ,037 44. .459 31. ,603 1. ,00 30. 52 c

ATOM 1912 CZ TYR A1227 -11. 698 44. ,534 31. 246 1. 00 31. 12 c

ATOM 1913 OH TYR A1227 -10. ,839 45. ,367 31. ,936 1. 00 36. 38 0

ATOM 1914 N LEU A1228 -12. 693 39. ,711 27. 685 1. 00 15. 28 N

ATOM 1915 CA LEU A1228 -11. 516 39. ,219 26. 981 1. 00 14. 49 c

ATOM 1916 C LEU A1228 -10. 352 40. ,208 26. 987 1. 00 17. 11 c

ATOM 1917 O LEU A1228 -10. 549 41. ,414 27. 142 1. 00 17. 83 0

( ( ATOM 1918 CB LEU A1228 -11.888 38.910 25.527 1.00 14.12 C

ATOM 1919 CG LEU A1228 -12 .865 37 .753 25 .261 1 .00 13 .92 C

ATOM 1920 CDl LEU A1228 -13 .624 37 .948 23 .943 1 .00 10 .23 C

ATOM 1921 CD2 LEU A1228 -12 .094 36 .444 25 .258 1 .00 12 .17 C

ATOM 1922 N ASP A1229 -9 .143 39 .673 26 .822 1 .00 18 .55 N

ATOM 1923 CA ASP A1229 -7 .920 40 .474 26 .730 1 .00 20 .12 C

ATOM 1924 C ASP A1229 -7 .851 40 .924 25 .281 1 .00 19 .92 C

ATOM 1925 O ASP A1229 -8 .569 40 .412 24 .421 1 .00 17 .62 0

ATOM 1926 CB ASP A1229 -6 .663 39 .610 26 .909 1 .00 24 .26 c

ATOM 1927 CG ASP A1229 -6 .433 39 .146 28 .325 1 .00 28 .55 c

ATOM 1928 OD1 ASP A1229 -6 .778 39 .876 29 .276 1 .00 29 .81 0

ATOM 1929 OD2 ASP A1229 -5 .839 38 .047 28 .463 1 .00 31 .53 0

ATOM 1930 N GLN A1230 -6 .969 41 .872 25 .008 1 .00 19 .35 N

ATOM 1931 CA GLN A1230 -6 .763 42 .324 23 .642 1 .00 19 .09 C

ATOM 1932 C GLN A1230 -5 .863 41 .281 22 .995 1 .00 19 .65 C

ATOM 1933 O GLN A1230 -4 .899 40 .824 23 .619 1 .00 20 .73 O

ATOM 1934 CB GLN A1230 -6 .073 43 .690 23 .637 1 .00 20 .64 C

ATOM 1935 CG GLN A1230 -6 .983 44 .782 24 .149 1 .00 21 .75 C

ATOM 1936 CD GLN A1230 -8 .283 44 .825 23 .368 1 .00 21 .59 C

ATOM 1937 OEl GLN A1230 -8 .281 45 .131 22 .182 1 .00 24 .35 0

ATOM 1938 NE2 GLN A1230 -9 .391 44 .488 24 .020 1, .00 22 .50 N

ATOM 1939 N PRO A1231 -6 .197 40, .834 21 .769 1, .00 16 .99 N

ATOM 1940 CA PRO A1231 -5 .347 39 .832 21 .116 1, .00 18 .20 C

ATOM 1941 C PRO A1231 -3 .942 40, .405 20 .946 1, .00 19 .74 C

ATOM 1942 O PRO A1231 -3 .751 41 .620 21 .013 1, .00 18 .09 O

ATOM 1943 CB PRO A1231 -6 .033 39 .634 19 .760 1, ,00 16 .76 C

ATOM 1944 CG PRO A1231 -7 .484 39, .916 20 .078 1. ,00 15 .87 C

ATOM 1945 CD PRO A1231 -7 .384 41, .135 20 .948 1, .00 16 .33 c

ATOM 1946 N ASP A1232 -2, .960 39, .538 20 .733 1. ,00 21 .93 N

ATOM 1947 CA ASP A1232 -1, .585 40. .001 20, .549 1. ,00 25, .50 C

ATOM 1948 C ASP A1232 -1, .469 40, .955 19, .361 1. .00 24, .87 C

ATOM 1949 O ASP A1232 -1, .969 40. .678 18, .266 1. .00 24, .26 O

ATOM 1950 CB ASP A1232 -0. .629 38. .816 20. .381 1. ,00 27, .71 C

ATOM 1951 CG ASP A1232 -0, ,542 37. .960 21. .633 1. ,00 34. .82 C

ATOM 1952 OD1 ASP A1232 -0. .333 38. .525 22. .733 1. ,00 37. .79 O

ATOM 1953 OD2 ASP A1232 -0, .698 36. .724 21, .522 1. ,00 39, .00 O

ATOM 1954 N ASN A1233 -0. .812 42. .085 19. .602 1. 00 25. .72 N

ATOM 1955 CA ASN A1233 -0, .601 43. ,118 18. ,594 1. 00 25. .21 C

ATOM 1956 C ASN A1233 -1, .869 43, ,695 17. .980 1. ,00 23. ,17 C

ATOM 1957 O ASN A1233 -1. ,911 44. ,043 16. ,799 1. 00 20. .26 O

ATOM 1958 CB ASN A1233 0. ,357 42. ,623 17, ,517 1. 00 30. .47 C

ATOM 1959 CG ASN A1233 1. .774 42. ,510 18. .029 1. 00 37. .56 C

ATOM 1960 ODl ASN A1233 2. ,101 41. ,598 18. ,795 1. 00 41. ,20 O

ATOM 1961 ND2 ASN A1233 2. 617 43. ,463 17. ,648 1. 00 42. ,78 N

ATOM 1962 N CYS A1234 -2. ,903 43. ,801 18. ,804 1. 00 20. .25 N

ATOM 1963 CA CYS A1234 -4. 171 44. 355 18. ,363 1. 00 19. ,24 C

ATOM 1964 C CYS A1234 -4. 020 45. 866 18. 132 1. 00 18. 20 C

ATOM 1965 .0 CYS A1234 -3. 440 46. 574 18. ,963 1. 00 16. ,21 O

ATOM 1966 CB CYS A1234 -5. 239 44. 098 19. 424 1. 00 17. 28 C

ATOM 1967 SG CYS A1234 -6. ,857 44. 695 18. ,948 1. 00 19. ,67 S

ATOM 1968 N PRO A1235 -4. 491 46. 371 16. 977 1. 00 16. 85 N

ATOM 1969 CA PRO A1235 -4. 386 47. 804 16. 694 1. 00 15. 79 C

ATOM 1970 C PRO A1235 -5. 121 48. 599 17. 767 1. 00 18. 16 C

ATOM 1971 O PRO A1235 -6. 247 48. 260 18. 129 1. 00 18. 78 O

ATOM 1972 CB PRO A1235 -5. 080 47. 931 15. 344 1. 00 15. 52 C

ATOM 1973 CG PRO A1235 -4. 786 46. 616 14. 698 1. 00 17. 70 C

ATOM 1974 CD PRO A1235 -5. 070 45. 657 15. 828 1. 00 16. 83 C ATOM 1975 N GLU A1236 -4.481 49.652 18.272 1.00 17.17 N

ATOM 1976 CA GLU A1236 -5 .056 50 .502 19 .318 1 .00 16 .70 C

ATOM 1977 C GLU A1236 -6 .473 50 .985 19 .017 1 .00 16 .18 C

ATOM 1978 O GLU A1236 -7 .319 51 .042 19 .906 1 .00 16 .28 O

ATOM 1979 CB GLU A1236 -4 .152 51 .714 19 .557 1 .00 20 .74 C

ATOM 1980 CG GLU A1236 -4 .630 52 .644 20 .661 1 .00 27 .71 C

ATOM 1981 CD GLU A1236 -3 .737 53 .868 20 .841 1 .00 33 .11 C

ATOM 1982 OEl GLU A1236 -2 .518 53 .780 20 .563 1 .00 32 .23 O

ATOM 1983 OE2 GLU A1236 -4 .265 54 .921 21 .266 1 .00 35 .67 O

ATOM 1984 N ARG A1237 -6 .717 51 .345 17 .763 1 .00 15 .15 N

ATOM 1985 CA ARG A1237 -8 .027 51 .812 17 .332 1 .00 15 .41 C

ATOM 1986 C ARG A1237 -9 .110 50 .751 17 .564 1 .00 15 .88 C

ATOM 1987 O ARG A1237 -10 .209 51 .076 18 .025 1 .00 12 .63 O

ATOM 1988 CB ARG A1237 -7 .964 52 .210 15 .859 1 .00 17 .65 C

ATOM 1989 CG ARG A1237 -9 .211 52 .871 15 .346 1 .00 23 .19 C

ATOM 1990 CD ARG A1237 -8 .884 53 .753 14 .162 1 .00 27 .34 C

ATOM 1991 NE ARG A1237 10 .064 54 .469 13 .702 1 .00 28 .59 N

ATOM 1992 CZ ARG A1237 10 .212 54 .949 12 .475 1 00 30 .30 C

ATOM 1993 NHl ARG A1237 -9 .248 54 .795 11 .571 1 00 31 .29 N

ATOM 1994 NH2 ARG A1237 11 .336 55 .568 12 .148 1 .00 32 .18 N

ATOM 1995 N VAL A1238 -8 .798 49 .491 17 .260 1 00 14 .26 N

ATOM 1996 CA VAL A1238 -9 .762 48 .402 17 458 1 00 14 .58 C

ATOM 1997 C VAL A1238 -9 .921 48 .131 18 .960 1 00 15 .20 C

ATOM 1998 O VAL A1238 11 027 47 .923 19 445 1 00 13 .05 O

ATOM 1999 CB VAL A1238 -9 360 47 113 16 700 1 00 13 .92 C

ATOM 2000 CGI VAL A1238 10 487 46 .080 16 776 1 00 13 .51 C

ATOM 2001 CG2 VAL A1238 -9 069 47 429 15 238 1 00 16 .13 C

ATOM 2002 N THR A1239 -8 813 48 149 19 696 1 00 15 .63 N

ATOM 2003 CA THR A1239 -8 863 47 957 21 141 1 00 15 .03 C

ATOM 2004 C THR A1239 -9 825 48 967 21 783 1 00 14 39 C

ATOM 2005 O THR A1239 10 619 48 610 22 660 1 00 13 53 0

ATOM 2006 CB THR A1239 -7 457 48 109 21 749 1 00 17 01 c

ATOM 2007 OG1 THR A1239 -6 661 46 991 21 343 1 00 15 69 o

ATOM 2008 CG2 THR A1239 -7 513 48 178 23 264 1 00 17 27 c

ATOM 2009 N ASP A1240 -9 752 50 222 21 335 1 00 15 09 N

ATOM 2010 CA ASP A1240 10 623 51 280 21 847 1 00 13 90 c

ATOM 2011 C ASP A1240 12 091 50 946 21 600 1 00 12 97 c

ATOM 2012 O ASP A1240 12 930 51 191 22 459 1 00 12 22 0

ATOM 2013 CB ASP A1240 10 287 52 629 21 202 1 00 17 92 c

ATOM 2014 CG ASP A1240 -8 900 53 154 21 595 1 00 21 79 c

ATOM 2015 ODl ASP A1240 -8 385 52 801 22 683 1 00 18 57 o

ATOM 2016 OD2 ASP A1240 -8 335 53 944 20 809 1 00 25 97 o

ATOM 2017 N LEU A1241 12 398 50 390 20 429 1 00 12 33 N

ATOM 2018 CA LEU A1241 13 777 50 006 20 114 1 00 13 56 c

ATOM 2019 C LEU A1241 14 255 48 903 21 065 1. 00 13 17 c

ATOM 2020 O LEU A1241 15 356 48 980 21 608 1 00 14 66 o

ATOM 2021 CB LEU A1241 13 891 49 540 18 658 1. 00 10 77 c

ATOM 2022 CG LEU A1241 13 598 50 590 17 589 1. 00 12 12 c

ATOM 2023 CDl LEU A1241 13 689 49 961 16 201 1. 00 16 33 c

ATOM 2024 CD2 LEU A1241 14 579 51 761 17 731 1. 00 12 34 c

ATOM 2025 N MET A1242 13. 424 47 882 21. 276 1. 00 13 46 N

ATOM 2026 CA MET A1242 13 779 46 785 22 181 1. 00 13 18 c

ATOM 2027 C MET A1242 14. 054 47 291 23. 596 1. 00 13 91 c

ATOM 2028 O MET A1242 14. 948 46. 789 24. 273 1. 00 13. 39 o

ATOM 2029 CB MET A1242 12. 670 45. 723 22. 232 1. 00 12 26 c

ATOM 2030 CG MET A1242 12. 548 44. 859 20. 985 1. 00 14. 94 c

ATOM 2031 SD MET A1242 11. 242 43. 602 21. 184 1. 00 17. 36 s

( ATOM 2032 CE MET A1242 -10.197 43.962 19.800 1.00 14.96 C

ATOM 2033 N ARG A1243 -13 .287 48 .284 24 .044 1 .00 13 .24 N

ATOM 2034 CA ARG A1243 -13 .481 48 .839 25 .386 1 .00 15 .64 C

ATOM 2035 C ARG A1243 -14 .882 49 .449 25 .519 1 .00 15 .13 C

ATOM 2036 O ARG A1243 -15 .534 49 .319 26 .556 1 .00 15 .61 0

ATOM 2037 CB ARG A1243 -12 .410 49 .896 25 .694 1 .00 13 .50 C

ATOM 2038 N MET A1244 -15 .332 50 .112 24 .457 1 .00 16 .58 N

ATOM 2039 CA MET A1244 -16 .660 50 .733 24 .414 1 .00 13 .68 C

ATOM 2040 C MET A1244 -17 .770 49 .671 24 .468 1 .00 13 .59 C

ATOM 2041 O MET A1244 -18 .770 49 .831 25 .160 1 .00 13 .56 O

ATOM 2042 CB MET A1244 -16 .814 51 .525 23 .117 1 .00 13 .91 C

ATOM 2043 CG MET A1244 -15 .917 52 .748 22 .999 1 .00 15 .74 C

ATOM 2044 SD MET A1244 -15 .990 53 .419 21 .338 1 .00 15 .59 S

ATOM 2045 CE MET A1244 -17 .375 54 .563 21 .501 1 .00 24 .00 C

ATOM 2046 N CYS A1245 -17 .572 48 .586 23 .726 1 .00 13 .80 N

ATOM 2047 CA CYS A1245 -18 .543 47 .493 23 .646 1 .00 12 .97 C

ATOM 2048 C CYS A1245 -18 .681 46 .663 24 .920 1 .00 12 .85 C

ATOM 2049 O CYS A1245 -19 .762 46 .130 25 .206 1 .00 10 .17 O

ATOM 2050 CB CYS A1245 -18 .169 46 .557 22 .496 1 .00 10 .26 C

ATOM 2051 SG CYS A1245 -18 .189 47 .291 20 .860 1 .00 11 .32 S

ATOM 2052 N TRP A1246 -17, .592 46 .555 25 .683 1 .00 12 .53 N

ATOM 2053 CA TRP A1246 -17 .591 45 .739 26 .899 1 .00 11 .52 C

ATOM 2054 C TRP A1246 -17 .874 46 .418 28 .236 1 .00 12 .50 C

ATOM 2055 O TRP A1246 -17, .565 45 .877 29 .298 1 .00 12 .42 O

ATOM 2056 CB TRP A1246 -16 .318 44 .891 26 .960 1 .00 8 .38 C

ATOM 2057 CG TRP A1246 -16, .223 43 .943 25 .789 1, .00 9 .61 C

ATOM 2058 CDl TRP A1246 -17. .258 43, .489 25 .015 1, .00 9, .89 C

ATOM 2059 CD2 TRP A1246 -15, .033 43 .381 25 .230 1, .00 11 .57 C

ATOM 2060 NΞl TRP A1246 -16, .786 42, .691 24 .004 1, .00 10 .12 N

ATOM 2061 CE2 TRP A1246 -15. .421 42, .605 24, .111 1, .00 12, .44 C

ATOM 2062 CE3 TRP A1246 -13, .671 43, .460 25 .560 1, .00 12 .61 c

ATOM 2063 CZ2 TRP A1246 -14. .499 41, .911 23, .323 1, .00 12, .42 c

ATOM 2064 CZ3 TRP A1246 -12. .755 42. .769 24, .773 1, .00 13, .83 c

ATOM 2065 CH2 TRP A1246 -13. .175 42, .006 23, .666 1, .00 12, .52 c

ATOM 2066 N GLN A1247 -18. .467 47. .601 28, .188 1. .00 11, .25 N

ATOM 2067 CA GLN A1247 -18. ,820 48. .293 29. .416 1. .00 13. .99 C

ATOM 2068 C GLN A1247 -19. .901 47. ,457 30. .078 1. .00 13. .47 C

ATOM 2069 O GLN A1247 -20. ,753 46. .894 29. .389 1. .00 11. ,87 O

ATOM 2070 CB GLN A1247 -19. ,314 49. ,694 29. .099 1. ,00 14. ,09 C

ATOM 2071 CG GLN A1247 -18. ,226 50. .517 28. .455 1. .00 20. .53 C

ATOM 2072 CD GLN A1247 -18. ,647 51. ,924 28. .223 1. .00 22. ,42 C

ATOM 2073 OEl GLN A1247 -18. ,670 52. ,731 29. .154 1. ,00 27. ,57 0

ATOM 2074 NE2 GLN A1247 -18. ,990 52. ,245 26. .976 1. ,00 22. ,34 N

ATOM 2075 N PHE A1248 -19. ,860 47, ,367 31. .406 1. ,00 12, ,69 N

ATOM 2076 CA PHE A1248 -20. 829 46. ,557 32. ,143 1. ,00 12. ,27 C

ATOM 2077 C PHE A1248 -22. ,268 47, ,051 32. .023 1. ,00 14. ,10 C

ATOM 2078 0 PHE A1248 -23. ,197 46. ,256 31, .842 1. ,00 14. ,17 O

ATOM 2079 CB PHE A1248 -20. 421 46. 450 33. ,613 1. 00 13. 71 C

ATOM 2080 CG PHE A1248 -21. ,126 45. ,349 34. ,349 1. ,00 14. ,53 C

ATOM 2081 CDl PHE A1248 -20. 637 44. 048 34. ,304 1. 00 14. 60 C

ATOM 2082 CD2 PHE A1248 -22. 299 45. 606 35. 053 1. 00 15. 56 C

ATOM 2083 CEl PHE A1248 -21. 306 43. 016 34. ,956 1. 00 17. 31 c

ATOM 2084 CE2 PHE A1248 -22. 968 44. 592 35. ,700 1. 00 16. 54 c

ATOM 2085 CZ PHE A1248 -22. 475 43. 293 35. 651 1. 00 16. 25 c

ATOM 2086 N ASN A1249 -22. 446 48. 364 32. ,126 1. 00 13. 30 N

ATOM 2087 CA ASN A1249 -23. 765 48. 982 32. 023 1. 00 13. 42 c

ATOM 2088 C ASN A1249 -24. 120 49. 076 30. 542 1. 00 13. 16 c

b°\ ATOM 2089 O ASN A1249 -23.492 49.829 29.796 1.00 11.65 O

ATOM 2090 CB ASN A1249 -23 .720 50 .387 32 .638 1 .00 15 .34 C

ATOM 2091 CG ASN A1249 -25 .083 51 .068 32 .678 1 .00 15 .16 C

ATOM 2092 OD1 ASN A1249 -26 .050 50 .612 32 .061 1 .00 13 .36 O

ATOM 2093 ND2 ASN A1249 -25 .158 52 .180 33 .402 1 .00 15 .50 N

ATOM 2094 N PRO A1250 -25 .145 48 .319 30 .103 1 .00 11 .96 N

ATOM 2095 CA PRO A1250 -25 .569 48 .334 28 .697 1 .00 11 .31 C

ATOM 2096 C PRO A1250 -25 .890 49 .741 28 .181 1 .00 11 .76 C

ATOM 2097 O PRO A1250 -25 .692 50 .044 27 .004 1 .00 8 .03 O

ATOM 2098 CB PRO A1250 -26 .790 47 .403 28 .692 1 .00 11 .35 C

ATOM 2099 CG PRO A1250 -27 .259 47 .390 30 .131 1 .00 10 .68 C

ATOM 2100 CD PRO A1250 -25 .968 47 .387 30 .893 1 .00 13 .41 C

ATOM 2101 N LYS A1251 -26 .361 50 .604 29 .072 1 .00 12 .59 N

ATOM 2102 CA LYS A1251 -26 .703 51 .975 28 .703 1 .00 14 .75 C

ATOM 2103 C LYS A1251 -25 .505 52 .865 28 .350 1 .00 13 .43 C

ATOM 2104 O LYS A1251 -25 .667 53 .914 27 .738 1 .00 12 .58 O

ATOM 2105 CB LYS A1251 -27 .540 52 .616 29 .809 1 .00 15 .57 C

ATOM 2106 CG LYS A1251 -28 .870 51 .906 30 .019 1 .00 20 .29 c

ATOM 2107 CD LYS A1251 -29 .697 52 .564 31 .108 1 .00 28 .27 c

ATOM 2108 CE LYS A1251 -30 .963 51 .761 31 .381 1 .00 31 .20 c

ATOM 2109 NZ LYS A1251 -31 .846 51 .663 30 .181 1, .00 35 .22 N

ATOM 2110 N MET A1252 -24 .302 52 .439 28 .726 1 .00 13 .91 N

ATOM 2111 CA MET A1252 -23. .096 53 .217 28 .447 1 .00 12 .68 C

ATOM 2112 C MET A1252 -22 .383 52 .783 27 .165 1, .00 13, .65 C

ATOM 2113 O MET A1252 -21, .451 53 .446 26 .717 1, .00 14, .31 O

ATOM 2114 CB MET A1252 -22, .143 53 .150 29 .641 1 .00 10 .68 C

ATOM 2115 CG MET A1252 -22, .738 53 .710 30 .933 1, .00 12, .13 c

ATOM 2116 SD MET A1252 -23, .216 55 .455 30 .752 1. .00 13, .40 s

ATOM 2117 CE MET A1252 -24, .391 55 .627 32 .109 1, .00 11, .66 c

ATOM 2118 N ARG A1253 -22. .823 51, .662 26 .587 1. .00 11, .57 N

ATOM 2119 CA ARG A1253 -22, .255 51 .147 25 .342 1, .00 8, .34 C

ATOM 2120 C ARG A1253 -22, .735 52, .006 24, .170 1. .00 11, .23 C

ATOM 2121 O ARG A1253 -23. .829 52, .579 24, .211 1. .00 10, .92 O

ATOM 2122 CB ARG A1253 -22. .688 49 .690 25, .126 1. .00 7, .62 C

ATOM 2123 CG ARG A1253 -22. ,287 48, .774 26, .254 1. .00 4. .60 c

ATOM 2124 CD ARG A1253 -22. .676 47, .327 26, .013 1. .00 9. .61 c

ATOM 2125 NE ARG A1253 -22. ,565 46, .593 27, .273 1. ,00 11. .66 N

ATOM 2126 CZ ARG A1253 -23. ,418 45. .660 27. .675 1. ,00 9. ,45 C

ATOM 2127 NHl ARG A1253 -24. ,433 45, .319 26, ,904 1. ,00 8. .00 N

ATOM 2128 NH2 ARG A1253 -23. ,333 45, .171 28. ,900 1. 00 9. ,27 N

ATOM 2129 N PRO A1254 -21. 922 52. .110 23. .108 1. 00 10. ,65 N

ATOM 2130 CA PRO A1254 -22. ,308 52. .913 21. .946 1. ,00 11, ,45 C

ATOM 2131 C PRO A1254 -23. ,398 52. .232 21. .109 1. 00 11. 23 C

ATOM 2132 O PRO A1254 -23. ,753 51, .078 21. .355 1. ,00 11. ,68 O

ATOM 2133 CB PRO A1254 -21. ,000 53. .006 21. .169 1. 00 13. ,77 C

ATOM 2134 CG PRO A1254 -20. 386 51. .664 21, ,423 1. 00 11. 41 C

ATOM 2135 CD PRO A1254 -20. ,605 51. .481 22. .902 1. 00 9. ,52 C

ATOM 2136 N THR A1255 -23. 925 52. .957 20. ,129 1. 00 10. 62 N

ATOM 2137 CA THR A1255 -24. .934 52. .414 19. .233 1. 00 10. .05 C

ATOM 2138 C THR A1255 -24. 207 52. .082 17. ,944 1. 00 8. 24 C

ATOM 2139 O THR A1255 -23. 093 52. ,553 17. ,718 1. 00 8. 46 O

ATOM 2140 CB THR A1255 -26. 035 53. .433 18. .923 1. 00 9. 01 C

ATOM 2141 OG1 THR A1255 -25. 481 54. ,519 18. ,176 1. 00 10. 43 O

ATOM 2142 CG2 THR A1255 -26. 626 53. ,976 20. 213 1. 00 10. 10 c

ATOM 2143 N PHE A1256 -24. 827 51. ,277 17. ,093 1. 00 5. 99 N

ATOM 2144 CA PHE A1256 -24. 190 50. ,909 15. 839 1. 00 8. 13 c

ATOM 2145 C PHE A1256 -23. 953 52. ,101 14. ,911 1. 00 9. 20 C

l ATOM 2146 O PHE A1256 -22.946 52.151 14.207 1.00 9.25 O

ATOM 2147 CB PHE A1256 -24 .955 49 .767 15 .175 1 .00 7 .23 C

ATOM 2148 CG PHE A1256 -24 .727 48 .438 15 .845 1 .00 7 .82 C

ATOM 2149 CDl PHE A1256 -23 .488 47 .796 15 .738 1 .00 7 .14 C

ATOM 2150 CD2 PHE A1256 -25 .729 47 .835 16 .598 1 .00 6 .95 C

ATOM 2151 CEl PHE A1256 -23 .256 46 .563 16 .376 1 .00 4 .77 C

ATOM 2152 CE2 PHE A1256 -25 .508 46 .608 17 .237 1 .00 8 .52 C

ATOM 2153 CZ PHE A1256 -24 .266 45 .973 17 .124 1 .00 7 .60 C

ATOM 2154 N LEU A1257 -24 .873 53 .065 14 .920 1 .00 10 .06 N

ATOM 2155 CA LEU A1257 -24 .710 54 .269 14 .106 1 .00 10 .24 C

ATOM 2156 C LEU A1257 -23 .492 55 .070 14 .597 1 .00 8 .72 C

ATOM 2157 O LEU A1257 -22 .760 55 .644 13 .793 1 .00 8 .58 O

ATOM 2158 CB LEU A1257 -25 .984 55 .129 14 .154 1 .00 11 .20 C

ATOM 2159 CG LEU A1257 -27 .122 54 .564 13 .304 1 .00 9 .91 C

ATOM 2160 CDl LEU A1257 -28 .409 55 .360 13 .516 1 .00 11 .22 C

ATOM 2161 CD2 LEU A1257 -26 .692 54 .591 11 .828 1 .00 8 .97 C

ATOM 2162 N GLU A1258 -23 .286 55 .098 15 .913 1 .00 6 .32 N

ATOM 2163 CA GLU A1258 -22 .153 55 .800 16 .501 1 .00 8 .82 C

ATOM 2164 C GLU A1258 -20 .829 55 .144 16 .105 1 .00 10 .20 C

ATOM 2165 O GLU A1258 -19 .826 55 .835 15 .925 1 .00 9 .85 O

ATOM 2166 CB GLU A1258 -22 .293 55 .873 18 .020 1 .00 12 .10 C

ATOM 2167 CG GLU A1258 -23 .410 56 .800 18 .451 1 .00 14 .32 C

ATOM 2168 CD GLU A1258 -23 .685 56 .770 19 .934 1 .00 16 .47 C

ATOM 2169 OEl GLU A1258 -23, .127 55, .905 20 .636 1, .00 14 .75 O

ATOM 2170 OE2 GLU A1258 -24 .478 57 .616 20 .397 1 .00 19 .76 O

ATOM 2171 N ILE A1259 -20, .833 53, .816 15 .962 1 .00 8 .63 N

ATOM 2172 CA ILE A1259 -19, .630 53, .086 15 .549 1, .00 8, .79 C

ATOM 2173 C ILE A1259 -19, .310 53 .464 14 .104 1 .00 9 .37 C

ATOM 2174 O ILE A1259 -18, .166 53, .783 13 .781 1, .00 11, .61 O

ATOM 2175 CB ILE A1259 -19. .822 51. .550 15 .641 1. ,00 8, .24 C

ATOM 2176 CGI ILE A1259 -19. .991 51, .123 17 .106 1, .00 7, .56 C

ATOM 2177 CG2 ILE A1259 -18. .640 50, .815 14 .972 1. .00 9. .29 C

ATOM 2178 CDl ILE A1259 -18. .782 51. ,373 17, .988 1. .00 12. .58 C

ATOM 2179 N VAL A1260 -20. .315 53. .425 13, .228 1. .00 8, .34 N

ATOM 2180 CA VAL A1260 -20. .089 53. .794 11, .830 1. .00 9. ,26 C

ATOM 2181 ^Ct VAL A1260 -19. .576 55. .237 11 .742 1. .00 10, .06 c

ATOM 2182 O VAL A1260 -18. .684 55. ,527 10, ,961 1. .00 10. .64 0

ATOM 2183 CB VAL A1260 -21. ,368 53. .653 10. ,961 1. .00 6, .98 c

ATOM 2184 CGI VAL A1260 -21. ,072 54. .028 9, .495 1. .00 8. .32 c

ATOM 2185 CG2 VAL A1260 -21. ,901 52. ,221 11. .030 1. ,00 6, .90 c

ATOM 2186 N ASN A1261 -20. 140 56. .131 12, .549 1. ,00 9, ,24 N

ATOM 2187 CA ASN A1261 -19. ,716 57. ,531 12. .541 1. ,00 8. .77 C

ATOM 2188 C ASN A1261 -18. 235 57. ,692 12. .918 1. 00 12. ,17 C

ATOM 2189 O ASN A1261 -17. 523 58. ,496 12. ,323 1. 00 10. ,30 0

ATOM 2190 CB ASN A1261 -20. ,570 58. ,341 13. ,506 1. ,00 12. .20 c

ATOM 2191 CG ASN A1261 -20. 260 59. ,821 13. ,447 1. 00 12. ,66 c

ATOM 2192 OD1 ASN A1261 -20. ,552 60. ,484 12. ,455 1. 00 11. 68 0

ATOM 2193 ND2 ASN A1261 -19. 670 60. ,347 14. ,510 1. 00 12. ,32 N

ATOM 2194 N LEU A1262 -17. 789 56. 923 13. ,909 1. 00 9. 81 N

ATOM 2195 CA LEU A1262 -16. 403 56. ,968 14. ,361 1. 00 13. ,12 C

ATOM 2196 C LEU A1262 -15. 434 56. 548 13. ,270 1. 00 14. ,03 C

ATOM 2197 O LEU A1262 -14. 288 57. 013 13. 236 1. 00 14. 30 O

ATOM 2198 CB LEU A1262 -16. 210 56. 033 15. ,558 1. 00 14. 31 C

ATOM 2199 CG LEU A1262 -16. 636 56. 497 16. 954 1. 00 15. 37 C

ATOM 2200 CDl LEU A1262 -16. 690 55. 301 17. 883 1. 00 13. 90 C

ATOM 2201 CD2 LEU A1262 -15. 670 57. 550 17. 483 1. 00 14. 51 C

ATOM 2202 N LEU A1263 -15. 899 55. 672 12. 380 1. 00 12. 19 N

7/ ATOM 2203 CA LEU A1263 -15.061 55.125 11.307 1.00 11.81 C

ATOM 2204 C LEU A1263 -15 .289 55 .658 9 .904 1 .00 11 .15 C

ATOM 2205 O LEU A1263 -14 .510 55 .355 8 .995 1 .00 11 .27 O

ATOM 2206 CB LEU A1263 -15 .256 53 .611 11 .253 1 .00 12 .80 C

ATOM 2207 CG LEU A1263 -15 .233 52 .842 12 .574 1 .00 10 .41 C

ATOM 2208 CDl LEU A1263 -15 .498 51 .365 12 .304 1 .00 11 .51 C

ATOM 2209 CD2 LEU A1263 -13 .899 53 .033 13 .266 1 .00 9 .61 C

ATOM 2210 N LYS A1264 -16 .347 56 .444 9 .724 1 .00 12 .59 N

ATOM 2211 CA LYS A1264 -16 .741 56 .964 8 .409 1 .00 13 .75 C

ATOM 2212 C LYS A1264 -15 .730 57 .724 7 .555 1 .00 13 .71 C

ATOM 2213 O LYS A1264 -15 .824 57 .703 6 .327 1 .00 13 .40 O

ATOM 2214 CB LYS A1264 -18 .011 57 .816 8 .540 1 .00 13 .76 C

ATOM 2215 CG LYS A1264 -17 .773 59 .210 9 .106 1 .00 17 .67 C

ATOM 2216 CD LYS A1264 -19 .064 60 .019 9 .191 1 .00 20 .30 C

ATOM 2217 CE LYS A1264 -18 .774 61 .459 9 .571 1 .00 19 .83 C

ATOM 2218 NZ LYS A1264 -18 .256 61 .577 10 .945 1 .00 22 .42 N

ATOM 2219 N ASP A1265 -14 .777 58 .401 8 .189 1 .00 16 .16 N

ATOM 2220 CA ASP A1265 -13 .788 59 .182 7 .448 1 .00 18 .36 C

ATOM 2221 C ASP A1265 -12 .631 58 .406 6 .844 1 .00 21 .07 C

ATOM 2222 O ASP A1265 -11 .813 58 .985 6 .132 1 .00 20 .92 O

ATOM 2223 CB ASP A1265 -13 .238 60 .319 8 .311 1 .00 20 .67 C

ATOM 2224 CG ASP A1265 -14 .297 61 .330 8 .689 1 .00 20 .58 C

ATOM 2225 OD1 ASP A1265 -15 .200 61 .593 7 .873 1 .00 23 .93 O

ATOM 2226 OD2 ASP A1265 -14 .226 61 .858 9 .813 1, .00 27 .42 O

ATOM 2227 N ASP A1266 -12 .552 57 .108 7 .114 1 .00 21 .65 N

ATOM 2228 CA ASP A1266 -11 .460 56 .313 6 .564 1, .00 24, .62 C

ATOM 2229 C ASP A1266 -11, .969 54 .999 5 .964 1. ,00 20. .63 C

ATOM 2230 O ASP A1266 -11 .433 53 .927 6 .254 1, .00 21, .15 0

ATOM 2231 CB ASP A1266 -10, .403 56 .056 7, .655 1, .00 31, .05 c

ATOM 2232 CG ASP A1266 -8, .975 55, .971 7, .097 1. .00 37. .21 c

ATOM 2233 OD1 ASP A1266 -8 .794 55, .788 5, .867 1, .00 38, .89 0

ATOM 2234 OD2 ASP A1266 -8, .023 56, .091 7, .902 1. .00 40. .39 0

ATOM 2235 N LEU A1267 -13. .000 55. .097 5. .121 1. ,00 16, ,82 N

ATOM 2236 CA LEU A1267 -13. ,613 53, .932 4. .478 1. .00 14. ,55 C

ATOM 2237 C LEU A1267 -13. .549 54. .046 2. .963 1. ,00 15. ,04 C

ATOM 2238 O LEU A1267 -13. ,232 55, .112 2. .431 1. ,00 12. .54 O

ATOM 2239 CB LEU A1267 -15. .078 53. ,799 4. ,912 1. ,00 14. ,71 C

ATOM 2240 CG LEU A1267 -15, ,332 53. .643 6. ,417 1. 00 15. ,15 c

ATOM 2241 CDl LEU A1267 -16. ,828 53. .695 6. ,697 1. ,00 13. ,05 c

ATOM 2242 CD2 LEU A1267 -14. ,735 52. .334 6. ,923 1. 00 13. 75 c

ATOM 2243 N HIS A1268 -13. 853 52. ,950 2. 268 1. 00 13. 80 N

ATOM 2244 CA HIS A1268 -13. ,826 52. .930 0. ,803 1. 00 15. 87 C

ATOM 2245 C HIS A1268 -14. ,811 53. ,969 0. 241 1. 00 15. 82 C

ATOM 2246 O HIS A1268 -15. 878 54. 197 0. 814 1. 00 12. 90 O

ATOM 2247 CB HIS A1268 -14. 152 51. ,519 0. 290 1. 00 16. 12 c

ATOM 2248 CG HIS A1268 -13. 853 51. ,320 -1. 163 1. 00 17. 81 c

ATOM 2249 NDl HIS A1268 -14. 791 51. ,528 -2. 152 1. 00 15. 02 N

ATOM 2250 CD2 HIS A1268 -12. 718 50. 948 -1. 800 1. 00 18. 53 C

ATOM 2251 CEl HIS A1268 -14. 248 51. 293 -3. 332 1. 00 15. 90 c

ATOM 2252 NE2 HIS A1268 -12. 989 50. 939 -3. 145 1. 00 17. 46 N

ATOM 2253 N PRO A1269 -14. 452 54. 628 -0. 879 1. 00 16. 69 N

ATOM 2254 CA PRO A1269 -15. 291 55. 648 -1. 518 1. 00 17. 89 C

ATOM 2255 C PRO A1269 -16. 717 55. 210 -1. 810 1. 00 15. 83 C

ATOM 2256 O PRO A1269 -17. 629 56. 028 -1. 822 1. 00 16. 29 O

ATOM 2257 CB PRO A1269 -14. 533 55. 941 -2. 814 1. 00 17. 96 C

ATOM 2258 CG PRO A1269 -13. 120 55. 758 -2. 412 1. 00 19. 65 C

ATOM 2259 CD PRO A1269 -13. 186 54. 475 -1. 619 1. 00 18. 25 C

7 ATOM 2260 N SER A1270 -16.910 53.918 -2.041 1.00 15.34 N

ATOM 2261 CA SER A1270 -18 .238 53 .392 -2 .337 1 .00 15 .15 C

ATOM 2262 C SER A1270 -19 .163 53 .291 -1 .121 1 .00 14 .03 C

ATOM 2263 O SER A1270 -20 .384 53 .214 -1 .281 1 .00 15 .91 O

ATOM 2264 CB SER A1270 -18 .108 52 .016 -2 .995 1 .00 17 .13 C

ATOM 2265 OG SER A1270 -17 .452 51 .098 -2 .130 1 .00 18 .73 O

ATOM 2266 N PHE A1271 -18 .595 53 .298 0 .086 1 .00 13 .40 N

ATOM 2267 CA PHE A1271 -19 .402 53 .152 1 .308 1 .00 12 .06 C

ATOM 2268 C PHE A1271 -20 .644 54 .053 1 .428 1 .00 15 .30 C

ATOM 2269 O PHE A1271 -21 .747 53 .555 1 .705 1 .00 13 .93 O

ATOM 2270 CB PHE A1271 -18 .525 53 .231 2 .565 1 .00 11 .09 C

ATOM 2271 CG PHE A1271 -19 .225 52 .792 3 .831 1 .00 9 .23 C

ATOM 2272 CDl PHE A1271 -19 .239 51 .448 4 .207 1 .00 12 .16 C

ATOM 2273 CD2 PHE A1271 -19 .851 53 .721 4 .653 1 .00 10 .91 c

ATOM 2274 CEl PHE A1271 -19 .870 51 .037 5 .390 1 .00 10 .81 c

ATOM 2275 CE2 PHE A1271 -20 .489 53 .323 5 .844 1 .00 9 .58 c

ATOM 2276 CZ PHE A1271 -20, .495 51, .975 6. .208 1 .00 9 .27 c

ATOM 2277 N PRO A1272 -20 .492 55 .377 1 .218 1 .00 15 .65 N

ATOM 2278 CA PRO A1272 -21, .625 56, .307 1 .306 1, .00 15, .97 C

ATOM 2279 C PRO A1272 -22, .682 56 .017 0 .230 1 .00 16 .20 C

ATOM 2280 O PRO A1272 -23 .848 56 .394 0 .363 1. .00 15 .27 O

ATOM 2281 CB PRO A1272 -20, .973 57, .666 1 .037 1, .00 16, .29 C

ATOM 2282 CG PRO A1272 -19 .575 57 .482 1 .493 1 .00 18 .58 C

ATOM 2283 CD PRO A1272 -19, .239 56, .114 0. .973 1, .00 16, .22 C

ATOM 2284 N GLU A1273 -22, .263 55 .351 -0 .840 1, .00 15, .76 N

ATOM 2285 CA GLU A1273 -23, .170 55, .032 -1, .936 1, .00 17. .31 C

ATOM 2286 C GLU A1273 -24, .077 53, .845 -1 .641 1. .00 16, .03 C

ATOM 2287 O GLU A1273 -25 .136 53 .698 -2 .246 1, .00 15, .10 0

ATOM 2288 CB GLU A1273 -22, .372 54, .741 -3, .210 1. .00 21. .96 C

ATOM 2289 CG GLU A1273 -21, .516 55, .895 -3 .704 1. .00 29, .20 c

ATOM 2290 CD GLU A1273 -20, .735 55, .568 -4, .976 1. .00 33. .15 c

ATOM 2291 OEl GLU A1273 -21, .121 54, .630 -5 .709 1. .00 37, .52 0

ATOM 2292 OΞ2 GLU A1273 -19. .730 56, .258 -5, .246 1. .00 37. .53 0

ATOM 2293 N VAL A1274 -23, .663 53, .005 -0, .702 1. .00 16. .23 N

ATOM 2294 CA VAL A1274 -24, .415 51, .798 -0 .374 1. .00 13. .93 C

ATOM 2295 C VAL A1274 -24. .836 51. ,610 1, .070 1. .00 12. .29 C

ATOM 2296 O VAL A1274 -25. .623 50, ,720 1, .357 1, .00 13, .23 O

ATOM 2297 CB VAL A1274 -23. .598 50. .536 -0, .747 1. ,00 15. .13 c

ATOM 2298 CGI VAL A1274 -23. .390 50. .455 -2, ,264 1. .00 17. .69 c

ATOM 2299 CG2 VAL A1274 -22. .264 50. .539 0. ,001 1. .00 11. ,41 c

ATOM 2300 N SER A1275 -24. .328 52. ,429 1, .982 1. .00 11. .24 N

ATOM 2301 CA SER A1275 -24. ,636 52. .247 3. .392 1. .00 12. .02 c

ATOM 2302 C SER A1275 -25. .992 52. .714 3. .867 1. .00 12. .46 c

ATOM 2303 O SER A1275 -26. ,589 53, .616 3, .288 1. .00 11. .53 0

ATOM 2304 CB SER A1275 -23. .582 52. .941 4. .247 1, ,00 14. .00 c

ATOM 2305 OG SER A1275 -23. .775 54. .347 4. .231 1. ,00 11. .47 0

ATOM 2306 N PHE A1276 -26. .470 52. .088 4. .938 1. ,00 11. ,10 N

ATOM 2307 CA PHE A1276 -27. .728 52. .493 5. .549 1, ,00 11. .39 c

ATOM 2308 C PHE A1276 -27. ,465 53, ,838 6. .238 1. ,00 11, ,51 c

ATOM 2309 O PHE A1276 -28. .306 54. .727 6. .219 1. ,00 13, .57 0

ATOM 2310 CB PHE A1276 -28. .164 51, .474 6. .600 1. .00 10. .70 c

ATOM 2311 CG PHE A1276 -29. .210 51. .993 7. .543 1. ,00 11. .66 c

ATOM 2312 CDl PHE A1276 -30. .500 52. .254 7. .094 1, .00 11. .07 c

ATOM 2313 CD2 PHE A1276 -28. ,893 52. .265 8. .869 1. ,00 10. ,44 c

ATOM 2314 CEl PHE A1276 -31. .453 52. .785 7. .941 1. ,00 12, ,32 c

ATOM 2315 CΞ2 PHE A1276 -29. ,844 52. ,798 9. ,724 1. ,00 13. ,59 c

ATOM 2316 CZ PHE A1276 -31. .128 53. .059 9. .259 1. ,00 14, .46 c

13 ATOM 2317 N PHE A1277 -26.281 53.958 6.843 1.00 10.58 N

ATOM 2318 CA PHE A1277 -25 .849 55 .154 7 .571 1 .00 12 .05 C

ATOM 2319 C PHE A1277 -25 .959 56 .438 6 .747 1 .00 11 .27 C

ATOM 2320 O PHE A1277 -26. .443 57 .454 7 .248 1 .00 12 .47 O

ATOM 2321 CB PHE A1277 -24 .396 54 .964 8 .042 1 .00 13 .66 C

ATOM 2322 CG PHE A1277 -23 .824 56 .143 8 .787 1 .00 12, .33 C

ATOM 2323 CDl PHE A1277 -23 .213 57 .191 8 .100 1 .00 11 .88 C

ATOM 2324 CD2 PHE A1277 -23 .849 56 .182 10 .179 1 .00 11 .40 C

ATOM 2325 CEl PHE A1277 -22 .627 58 .264 8. .793 1, .00 12, .87 C

ATOM 2326 CE2 PHE A1277 -23 .267 57 .246 10 .879 1 .00 12 .66 C

ATOM 2327 CZ PHE A1277 -22 .655 58 .288 10 .186 1, .00 11, ,93 C

ATOM 2328 N HIS A1278 -25 .497 56 .389 5 .500 1 .00 13, .45 N

ATOM 2329 CA HIS A1278 -25 .538 57 .551 4 .614 1 .00 12 .81 C

ATOM 2330 C HIS A1278 -26 .843 57 .664 3 .824 1, .00 14, .33 C

ATOM 2331 O HIS A1278 -27 .045 58 .640 3 .099 1 .00 13, .36 O

ATOM 2332 CB HIS A1278 -24 .355 57, .538 3 .631 1, .00 12, .28 C

ATOM 2333 CG HIS A1278 -23 .013 57 .693 4 .284 1, .00 14, .96 C

ATOM 2334 NDl HIS A1278 -22 .228 56, .615 4 .631 1, .00 17, .31 N

ATOM 2335 CD2 HIS A1278 -22 .318 58, .798 4 .654 1, .00 11, .69 C

ATOM 2336 CEl HIS A1278 -21 .110 57 .045 5 .191 1 .00 12, .35 C

ATOM 2337 NE2 HIS A1278 -21, .140 58, .366 5, .218 1, ,00 15, .39 N

ATOM 2338 N SER A1279 -27 .726 56 .679 3, .962 1, .00 14, .65 N

ATOM 2339 CA SER A1279 -28, .995 56, .671 3, .228 1, .00 15, .48 C

ATOM 2340 C SER A1279 -30 .079 57, .585 3 .791 1, ,00 17, .07 C

ATOM 2341 O SER A1279 -30 .064 57 .947 4 .972 1, .00 15, .63 O

ATOM 2342 CB SER A1279 -29, .569 55, .257 3, .165 1, .00 12, .37 C

ATOM 2343 OG SER A1279 -30 .099 54, .893 4, .432 1, .00 13, .76 O

ATOM 2344 N GLU A1280 -31, .033 57, .937 2, ,931 1. .00 16. .51 N

ATOM 2345 CA GLU A1280 -32 .151 58, .792 3, .324 1, .00 18, ,88 C

ATOM 2346 C GLU A1280 -33 .007 58 .083 4 .366 1, .00 19. .45 C

ATOM 2347 O GLU A1280 -33, .669 58, .727 5, .178 1. .00 19. .43 O

ATOM 2348 CB GLU A1280 -33 .011 59, .140 2 .103 1, .00 20, .88 C

ATOM 2349 N GLU A1281 -32, .987 56, .751 4, .337 1. .00 17. .17 N

ATOM 2350 CA GLU A1281 -33, .757 55, .950 5, .281 1, .00 18, .39 C

ATOM 2351 C GLU A1281 -33, .294 56. .122 6, ,729 1, ,00 18. .40 C

ATOM 2352 O GLU A1281 -34, .075 55, .911 7, ,665 1. ,00 19. .35 O

ATOM 2353 CB GLU A1281 -33 .693 54, .476 4, ,888 1, .00 20, .20 C

ATOM 2354 CG GLU A1281 -34, .601 53, .575 5, .713 1. .00 22. .02 C

ATOM 2355 CD GLU A1281 -34, .628 52, .137 5, .219 1, .00 24. .98 C

ATOM 2356 OEl GLU A1281 -33, .834 51, .785 4, .321 1, .00 27. .09 O

ATOM 2357 OE2 GLU A1281 -35, .448 51, .354 5, .740 1. .00 27. .61 O

ATOM 2358 N ASN A1282 -32 .027 56, .490 6, ,918 1, .00 17. .57 N

ATOM 2359 CA ASN A1282 -31, .499 56. .694 8, .267 1. .00 18. .76 C

ATOM 2360 C ASN A1282 -32, .005 58, .036 8, .769 1. .00 22. .04 C

ATOM 2361 O ASN A1282 -31, ,302 59. .047 8. .702 1. .00 20. .86 O

ATOM 2362 CB ASN A1282 -29, .962 56, .654 8, .281 1. .00 12. .43 C

ATOM 2363 CG ASN A1282 -29 .383 56, .858 9, .673 1, .00 13. .92 C

ATOM 2364 OD1 ASN A1282 -30, .058 56, .645 10. .675 1. .00 14. .05 O

ATOM 2365 ND2 ASN A1282 -28 .130 57, .279 9. .738 1. .00 12, .60 N

ATOM 2366 N LYS A1283 -33, .240 58. .031 9. .262 1. .00 26. .60 N

ATOM 2367 CA LYS A1283 -33, .879 59, .235 9, ,769 1. .00 30. .37 C

ATOM 2368 C LYS A1283 -34, .418 59. .007 11. .172 1. ,00 33. .57 C

ATOM 2369 O LYS A1283 -34, .178 59. .912 12. .000 1. .00 36. .06 O

ATOM 2370 CB LYS A1283 -35 .018 59, .660 8, .839 1. .00 30. .48 C

TΞR 2371 LYS A1283

ATOM 2372 N GLY B 8 -19, .401 23, .262 22, .398 1. .00 34. .71 N

ATOM 2373 CA GLY B 8 -19, .781 24. .007 21. .212 1. ,00 32. .05 C ATOM 2374 C GLY B 8 -19.925 25.496 21.475 1,.00 29.46 C

ATOM 2375 O GLY B 8 -19 .608 25 .984 22 .563 1 .00 29 .30 O

ATOM 2376 N ASP B 9 -20 .419 26 .215 20 .472 1, .00 26 .80 N

ATOM 2377 CA ASP B 9 -20 .616 27 .654 20 .570 1 .00 23 .47 C

ATOM 2378 C ASP B 9 -21 .840 28 .030 21 .387 1, .00 21 .80 C

ATOM 2379 O ASP B 9 -21 .999 29 .192 21 .751 1, .00 20 .86 O

ATOM 2380 CB ASP B 9 -20 .729 28 .269 19 .174 1, .00 21, .23 c

ATOM 2381 CG ASP B 9 -19 .429 28 .197 18 .399 1, .00 21 .33 c

ATOM 2382 ODl ASP B 9 -18. .346 28 .190 19 .028 1, .00 18, .76 O

ATOM 2383 OD2 ASP B 9 -19 .493 28 .151 17 .159 1, .00 21 .26 0

ATOM 2384 N TYR B 10 -22 .694 27, .045 21 .670 1. .00 21, .39 N

ATOM 2385 CA TYR B 10 -23 .918 27 .271 22 .433 1, ,00 20, .06 C

ATOM 2386 C TYR B 10 -24 .026 26 .398 23 .673 1, .00 22 .21 C

ATOM 2387 O TYR B 10 -23 .472 25 .302 23 .736 1. .00 24, .09 O

ATOM 2388 CB TYR B 10 -25 .147 27 .034 21 .547 1, .00 20 .66 C

ATOM 2389 CG TYR B 10 -25 .150 27 .867 20 .292 1. .00 18, .82 C

ATOM 2390 CDl TYR B 10 -24 .480 27 .438 19 .150 1, ,00 16, .95 c

ATOM 2391 CD2 TYR B 10 -25, .768 29 .116 20 .266 1. .00 20, ,11 c

ATOM 2392 CEl TYR B 10 -24 .416 28 .232 18 .016 1, .00 15, .56 c

ATOM 2393 CΞ2 TYR B 10 -25, .711 29, .914 19 .134 1, .00 15, .54 c

ATOM 2394 CZ TYR B 10 -25 .033 29 .469 18 .021 1, .00 14, .46 c

ATOM 2395 OH TYR B 10 -24, .947 30, .258 16 .910 1. .00 15, ,70 0

ATOM 2396 N MET B 11 -24 .753 26 .901 24 .658 1, .00 22, .77 N

ATOM 2397 CA MET B 11 -24, .982 26, .181 25 .899 1. .00 25, .17 c

ATOM 2398 C MET B 11 -26 .491 26 .191 26 .141 1. .00 25, .60 c

ATOM 2399 O MET B 11 -27 .136 27 .238 26 .034 1, .00 24, .39 0

ATOM 2400 CB MET B 11 -24 .259 26 .864 27 .060 1. .00 25, .62 c

ATOM 2401 CG MET B 11 -24 .381 26 .120 28 .380 1, .00 31, .32 c

ATOM 2402 SD MET B 11 -23, .534 26, .949 29 .724 1. .00 36, .50 s

ATOM 2403 CE MET B 11 -24 .904 27 .580 30 .681 1, .00 34, .12 c

ATOM 2404 N ASN B 12 -27. .054 25, .027 26 .452 1. .00 26. .81 N

ATOM 2405 CA ASN B 12 -28, .485 24 .940 26 .719 1. .00 27, .68 C

ATOM 2406 C ASN B 12 -28, .693 25, .461 28, .136 1. ,00 28. ,15 C

ATOM 2407 O ASN B 12 -28, .244 24, .845 29 .105 1. .00 28, .94 0

ATOM 2408 CB ASN B 12 -28, .971 23. .496 26, .581 1. .00 30. .42 c

ATOM 2409 CG ASN B 12 -30, .484 23, .390 26 .500 1. ,00 34. .99 c

ATOM 2410 ODl ASN B 12 -31, .063 22 .386 26 .917 1, .00 41, .96 0

ATOM 2411 ND2 ASN B 12 -31, .132 24, .416 25, .949 1. .00 33. .05 N

ATOM 2412 N MET B 13 -29, .365 26 .604 28 .248 1. .00 28, .43 N

ATOM 2413 CA MET B 13 -29, .607 27, .235 29, .543 1. .00 29. ,77 C

ATOM 2414 C MET B 13 -30, .913 28, .036 29, .565 1. ,00 29. .71 C

ATOM 2415 O MET B 13 -31, .522 28, .273 28, .521 1. .00 29. ,49 O

ATOM 2416 CB MET B 13 -28, .426 28, .154 29, .902 1. .00 30. .13 C

ATOM 2417 CG MET B 13 -28. .086 29, .190 28, .836 1. .00 31. .87 C

ATOM 2418 SD MET B 13 -26, .747 30, .316 29, .310 1. .00 33. .97 S

ATOM 2419 CE MET B 13 -27. ,593 31, .383 30, .485 1. ,00 32. .25 C

TER 2420 MET B 13

HETATM 2421 PG ANP 300 -23. ,145 27, .941 12, .761 1. .00 17. ,52 P

HETATM 2422 OlG ANP 300 -21, .876 27, .274 12, .416 1. .00 15. .24 O

HETATM 2423 02G ANP 300 -23, .360 29 .256 12 .098 1. .00 17, .89 O

HETATM 2424 03G ANP 300 -23, .459 27, .935 14, .226 1. .00 14. .97 0

HETATM 2425 PB ANP 300 -25, .717 27 .429 11, .199 1. .00 15, .81 P

HETATM 2426 OIB ANP 300 -26, .674 26, .293 11, .308 1. .00 17. .35 0

HETATM 2427 02B ANP 300 -26, .217 28, .733 11, .662 1. .00 16. .19 0

HETATM 2428 N3B ANP 300 -24. ,316 26, .989 12, .017 1. .00 18, .38 N

HETATM 2429 PA ANP 300 -25, .948 27, .942 8, .400 1. .00 18. ,99 P

HETATM 2430 OlA ANP 300 -26. .778 26, .834 7. .937 1. .00 19. ,21 0

^•7J HETATM 2431 02A ANP 300 -26.582 29.287 8.531 1.00 16.32 O

HETATM 2432 03A ANP 300 -25 .165 27 .528 9 .733 1 .00 15 .88 O

HETATM 2433 05* ANP 300 -24 .678 28 .101 7 .421 1 .00 17 .56 O

HETATM 2434 C5* ANP 300 -23 .669 27 .085 7 .263 1 .00 17 .79 C

HETATM 2435 C4* ANP 300 -22 .487 27 .605 6 .467 1 .00 17 .26 C

HETATM 2436 04* ANP 300 -22 .928 27 .823 5 .132 1 .00 18 .37 O

HETATM 2437 C3* ANP 300 -21 .957 28 .965 6 .935 1 .00 17 .29 C

HETATM 2438 03* ANP 300 -20 .951 28 .858 7 .985 1 .00 17 .31 O

HETATM 2439 C2* ANP 300 -21 .296 29 .506 5 .697 1 .00 17 .44 C

HETATM 2440 02* ANP 300 -19 .959 28 .950 5 .501 1 .00 17 .81 O

HETATM 2441 CI* ANP 300 -22 .223 28 .964 4 .596 1 .00 15 .15 C

HETATM 2442 N9 ANP 300 -23 .181 30 .018 4 .173 1 .00 15 .52 N

HETATM 2443 C8 ANP 300 -24 .335 30 .419 4 .783 1 .00 11 .56 C

HETATM 2444 N7 ANP 300 -24 .980 31 .339 4 .114 1, .00 9, .82 N

HETATM 2445 C5 ANP 300 -24 .207 31 .565 3 .001 1 .00 12 .22 C

HETATM 2446 C6 ANP 300 -24 .350 32 .442 1 .894 1, .00 13 .39 C

HETATM 2447 N6 ANP 300 -25, .356 33 .322 1 .733 1. .00 13, .57 N

HETATM 2448 Nl ANP 300 -23 .388 32 .391 0 .967 1, .00 12 .99 N

HETATM 2449 C2 ANP 300 -22 .364 31 .548 1 .132 1, .00 13, .88 C

HETATM 2450 N3 ANP 300 -22 .114 30 .702 2 .104 1, .00 13 .00 N

HETATM 2451 C4 ANP 300 -23 .101 30 .762 3 .025 1, .00 11 .53 C

HETATM 2452 MG MG 301 -24, .995 30, .395 12 .100 1, .00 13, .67 MG

HETATM 2453 MG MG 302 -28 .443 29 .409 12 .576 1, .00 12 .06 MG

HETATM 2454 0 HOH 1 -25, .774 39 .491 19 .220 1, ,00 7, .84 O

HETATM 2455 0 HOH 2 -19. .253 48, .245 1 .882 1, .00 11, .01 O

HETATM 2456 0 HOH 3 -30 .541 42 .803 2 .732 1, .00 11, .93 O

HETATM 2457 0 HOH 4 -17, .585 50, .226 0, .955 1. .00 11, .85 O

HETATM 2458 0 HOH 5 -18 .485 41 .721 32 .252 1, .00 11, .92 O

HETATM 2459 0 HOH 6 -28, .153 40, .565 21 .827 1. .00 12, .11 O

HETATM 2460 0 HOH 7 -23, .467 35, .191 19, .263 1. .00 11, .93 O

HETATM 2461 0 HOH 8 -26, .502 58, .238 11 .882 1. .00 19, .64 O

HETATM 2462 0 HOH 9 -27, .733 52, ,334 15, .872 1. .00 12, .13 O

HETATM 2463 0 HOH 10 -26, .123 38, .874 24, .964 1. .00 7, ,77 O

HETATM 2464 0 HOH 11 -8, .636 37, .180 25, .670 1. .00 17, .47 O

HETATM 2465 0 HOH 12 -20, .285 29. .993 23, .705 1. .00 16. .61 O

HETATM 2466 0 HOH 13 -17, .893 33, .059 15, .436 1. .00 12. .07 O

HETATM 2467 0 HOH 14 -15. .319 40. .246 26, ,359 1. .00 14. .90 O

HETATM 2468 0 HOH 15 -27. .083 42. .600 0. .512 1. .00 11. .94 O

HETATM 2469 0 HOH 16 -14, .807 44, ,292 4, .036 1. .00 17. .43 0

HETATM 2470 0 HOH 17 -19. .627 58. .528 16, .899 1. .00 15. .89 0

HETATM 2471 0 HOH 18 -1, .423 41, .985 6, .913 1. .00 22, .95 0

HETATM 2472 0 HOH 19 -19. .528 46. .973 -0, .584 1. ,00 15. .52 0

HETATM 2473 0 HOH 20 -20. .019 36. .295 27, .490 1, ,00 14. .57 0

HETATM 2474 0 HOH 21 -27, .576 50, .344 18, .151 1. .00 12. .46 0

HETATM 2475 0 HOH 22 -39. .822 38. .118 17, .050 1. .00 20. .79 0

HETATM 2476 0 HOH 23 -17. .808 57. .044 4. .500 1. ,00 17. ,67 0

HETATM 2477 0 HOH 24 -29. .294 44, .022 27, ,154 1. .00 21. .54 0

HETATM 2478 0 HOH 25 -31. .616 36. ,043 -12. .363 1. 00 15. ,81 0

HETATM 2479 0 HOH 26 -15. .394 30, .292 17, .633 1. .00 19. .96 0

HETATM 2480 0 HOH 27 -20. .197 36, .802 -3, .351 1. ,00 12. .73 0

HETATM 2481 0 HOH 28 -17. .676 48. .746 32. .754 1. ,00 14. .99 0

HETATM 2482 0 HOH 29 -30. ,098 35. ,797 14. .820 1. ,00 17. .12 0

HETATM 2483 0 HOH 30 -16. .158 46. .056 0. .858 1. ,00 15. ,01 0

HETATM 2484 0 HOH 31 -27. .848 34, .090 6, .523 1. .00 30. .61 0

HETATM 2485 0 HOH 32 -24. .909 30. .146 14. .073 1. ,00 12, ,13 0

HETATM 2486 0 HOH 33 -17. .956 30. .495 16. .498 1. ,00 13. ,04 0

HETATM 2487 0 HOH 34 -25. .773 39. .212 22, .360 1. .00 12, .17 0

7 HETATM 2488 0 HOH 35 13.543 58.349 10.859 1.00 27.66 o

HETATM 2489 0 HOH 36 30 .137 49 .950 3 .700 1 .00 22 .88 o

HETATM 2490 0 HOH 37 32 .750 47 .729 22 .228 1 .00 11 .86 o

HETATM 2491 0 HOH 38 27 010 56 .711 17 .611 1 .00 22 .69 0

HETATM 2492 0 HOH 39 20 .498 45 .069 -2 .872 1 .00 22 .81 o

HETATM 2493 0 HOH, 40 16 .071 56 .685 2 .220 1 .00 17 .74 o

HETATM 2494 0 HOH 41 31 869 40 .709 3 .980 1 .00 17 .73 0

HETATM 2495 0 HOH 42 -4 626 40 .511 10 .678 1 00 22 .36 0

HETATM 2496 0 HOH 43 29 321 45 732 17 .107 1 00 29 37 0

HETATM 2497 0 HOH 44 30 540 33 .960 7 .968 1 .00 17 .21 0

HETATM 2498 0 HOH 45 33 789 40 .004 1 .977 1 00 19 .59 0

HETATM 2499 0 HOH 46 18 217 37 672 25 .875 1 00 17 27 o

HETATM 2500 0 HOH 47 29 956 51 967 14 .226 1 00 12 46 O

HETATM 2501 0 HOH 48 10 957 28 .182 7 .071 1 00 23 .69 0

HETATM 2502 0 HOH 49 -9 322 40 241 30 .634 1 00 25 .29 0

HETATM 2503 0 HOH 50 17 717 24 184 27 625 1 00 31 33 O

HETATM 2504 0 HOH 51 25 833 36 598 -5 417 1 00 18 58 o

HETATM 2505 0 HOH 52 24 958 30 786 10 .101 1 00 11 16 o

HETATM 2506 0 HOH 53 13 758 32 335 16 .729 1 00 13 05 0

HETATM 2507 0 HOH 54 -2 235 35 062 5 322 1 00 21 24 o

HETATM 2508 0 HOH 55 12 092 44 702 4 563 1 00 16 70 o

HETATM 2509 0 HOH 56 -9 426 34 374 25 .694 1 00 24 .41 o

HETATM 2510 0 HOH 57 -5 548 47 420 3 128 1 00 14 60 O

HETATM 2511 0 HOH 58 28 947 32 552 15 046 1 00 21 58 o

HETATM 2512 0 HOH 59 16 412 45 044 33 623 1 00 24 12 0

HETATM 2513 0 HOH 60 27 830 49 637 2 393 1 00 16 71 o

HETATM 2514 0 HOH 61 21 755 26 785 16 034 1 00 21 21 o

HETATM 2515 0 HOH 62 24 079 39 915 35 980 1 00 22 52 0

HETATM 2516 0 HOH 63 25 071 36 764 21 346 1 00 14 70 o

HETATM 2517 0 HOH 64 26 310 55 332 1 245 1 00 13 92 o

HETATM 2518 0 HOH 65 -4 818 51 604 15 442 1 00 15 89 o

HETATM 2519 0 HOH 66 32 138 55 378 11 812 1 00 18 67 o

HETATM 2520 0 HOH 67 23 285 38 869 -2 968 1 00 18 01 0

HETATM 2521 0 HOH 68 41 163 24 440 -8 200 1 00 39 02 0

HETATM 2522 0 HOH 69 25 003 21 151 -11 379 1 00 19 35 o

HETATM 2523 0 HOH 70 -5 854 39 844 13 060 1 00 19 74 o

HETATM 2524 0 HOH 71 20 230 50 081 32 908 1 00 28 01 0

HETATM 2525 0 HOH 72 24 781 44 284 32 568 1 00 15 41 o

HETATM 2526 0 HOH 73 40 970 44 661 21 723 1 00 25 03 o

HETATM 2527 0 HOH 74 22 250 30 062 9 917 1 00 18 16 0

HETATM 2528 0 HOH 75 25 618 26 417 14 961 1 00 22 87 o

HETATM 2529 0 HOH 76 27 506 30 897 6 497 1 00 20 28 0

HETATM 2530 0 HOH 77 -9 065 40 608 4 565 1 00 25 60 o

HETATM 2531 0 HOH 78 39 848 45 322 14 090 1 00 17 45 o

HETATM 2532 0 HOH 79 -9 014 29 332 0 704 1 00 26 19 o

HETATM 2533 0 HOH 80 22 501 30 067 -8 622 1 00 14 70 0

HETATM 2534 0 HOH 81 38 626 25 462 8 204 1 00 27 08 o

HETATM 2535 0 HOH 82 28 803 29 526 10 176 1 00 22 18 o

HETATM 2536 0 HOH 83 -4 221 41 649 16 774 1 00 21 33 o

HETATM 2537 0 HOH 84 28 766 20 848 -9 373 1 00 15 54 o

HETATM 2538 0 HOH 85 42 847 44 169 19 511 1 00 35 31 o

HETATM 2539 0 HOH 86 21 329 40 817 -4 041 1 00 30 53 0

HETATM 2540 0 HOH 87 10 564 51 426 6 540 1 00 22 00 0

HETATM 2541 0 HOH 88 10 852 42 363 3 645 1 00 23 89 o

HETATM 2542 0 HOH 89 24 313 22 710 -13 552 1 00 25 70 O

HETATM 2543 0 HOH 90 -8 680 32 671 23 249 1 00 23 73 O

HETATM 2544 0 HOH 91 -1 748 50 289 17 294 1 00 16 92 0

? HETATM 2545 0 HOH 92 17.641 60.212 17.549 1.00 23.14 0

HETATM 2546 0 HOH 93 31 .869 53 .961 14 .235 1 .00 16 .20 o

HETATM 2547 0 HOH 94 -8 .420 29 .263 20 .338 1 .00 24 .94 o

HETATM 2548 0 HOH 95 27 .790 29 .197 14 .905 1 .00 22 .29 0

HETATM 2549 0 HOH 96 -9 .630 43 .881 26 .842 1 .00 25 .15 o

HETATM 2550 0 HOH 97 18 .294 44 .536 31 .613 1 .00 20 .09 o

HETATM 2551 0 HOH 98 37 074 45 .922 3 .046 1 .00 34 .36 o

HETATM 2552 0 HOH 99 24 .042 32 .446 -13 .080 1 00 32 .94 o

HETATM 2553 0 HOH 100 24 .303 36 .601 -9 .763 1 .00 26 .02 0

HETATM 2554 0 HOH 101 0 .488 35 .544 5 .931 1 .00 29 .35 o

HETATM 2555 0 HOH 102 22 .140 42 .925 -2 .308 1 00 23 .75 0

HETATM 2556 0 HOH 103 29 044 24 .976 10 .206 1 00 24 .35 o

HETATM 2557 0 HOH 104 17 287 28 .527 10 .833 1 .00 39 .85 o

HETATM 2558 0 HOH 105 17 996 27 .697 15 .083 1 00 22 .10 0

HETATM 2559 0 HOH 106 13 646 45 .237 0 .250 1 .00 30 .12 o

HETATM 2560 0 HOH 107 11 552 45 .654 2 .165 1 00 22 .05 0

HETATM 2561 0 HOH 108 12 936 48 305 0 .743 1 00 22 .74 o

HETATM 2562 0 HOH 109 12 886 36 .891 -4 .625 1 00 25 48 0

HETATM 2563 0 HOH 110 38 173 41 750 8 .538 1 00 24 34 o

HETATM 2564 0 HOH 111 34 331 20 .259 -4 .965 1 00 24 .18 o

HETATM 2565 0 HOH 112 1 345 40 .469 6 .666 1 00 28 70 o

HETATM 2566 0 HOH 113 -3 099 43 .819 10 .687 1 00 23 .84 0

HETATM 2567 0 HOH 114 31 126 52 455 3 502 1 00 21 47 o

HETATM 2568 0 HOH 115 26 087 49 642 21 211 1 00 29 91 o

HETATM 2569 0 HOH 116 18 909 53 931 24 .722 1 00 20 10 0

HETATM 2570 0 HOH 117 14 745 53 028 26 592 1 00 22 16 o

HETATM 2571 0 HOH 118 -7 920 28 762 16 980 1 00 33 .70 o

HETATM 2572 0 HOH 119 21 815 23 179 -14 449 1 00 19 96 o

HETATM 2573 0 HOH 120 40 107 31 886 20 311 1 00 36 26 0

HETATM 2574 0 HOH 121 -4 630 42 416 14 234 1 00 29 55 o

HETATM 2575 0 HOH 122 0 172 42 800 22 208 1 00 38 54 o

HETATM 2576 0 HOH 123 31 050 43 360 -0 080 1 00 22 91 0

HETATM 2577 0 HOH 124 16 712 54 776 26 124 1 00 22 47 0

HETATM 2578 0 HOH 125 25 459 42 263 34 540 1 00 21 52 0

HETATM 2579 0 HOH 126 14 190 57 618 4 115 1 00 20 18 0

HETATM 2580 0 HOH 127 20 503 36 195 -6 145 1 00 33 84 0

HETATM 2581 0 HOH 128 10 161 31 691 1 933 1 00 28 78 0

HETATM 2582 0 HOH 129 36 005 48 987 4 630 1 00 22 96 o

HETATM 2583 0 HOH 130 31 050 17 843 11 034 1 00 40 47 o

HETATM 2584 0 HOH 131 12 399 53 130 24 286 1 00 27 24 0

HETATM 2585 0 HOH 132 19 201 28 079 12 729 1 00 22 80 0

HETATM 2586 0 HOH 133 20 971 55 652 24 277 1 00 28 95 0

HETATM 2587 0 HOH 134 20 271 25 244 -13 319 1 00 31 35 0

HETATM 2588 0 HOH 135 27 604 38 741 -5 639 1 00 27 89 0

HETATM 2589 0 HOH 136 17 428 58 781 -1 616 1 00 37 30 0

HETATM 2590 0 HOH 137 -4 055 47 610 21 558 1 00 26 92 0

HETATM 2591 0 HOH 138 33 509 49 460 20 224 1 00 29 93 0

HETATM 2592 0 HOH 139 34 306 53 661 15 407 1 00 31 45 0

HETATM 2593 0 HOH 140 40 102 31 288 -10 539 1 00 39 36 0

HETATM 2594 0 HOH 141 16 332 26 708 17 993 1 00 30 70 0

HETATM 2595 0 HOH 142 11 579 53 603 17 800 1 00 28 28 0

HETATM 2596 0 HOH 143 33 592 31 757 21 483 1 00 34 69 0

HETATM 2597 0 HOH 144 22 664 62 062 11 392 1 00 25 97 0

HETATM 2598 0 HOH 145 30 210 27 221 -13 245 1 00 27 90 0

HETATM 2599 0 HOH 146 39 425 46 631 10 842 1 00 29 04 0

HETATM 2600 0 HOH 147 34 152 20 554 18 560 1 00 34 10 0

HETATM 2601 0 HOH 148 28 914 54 632 17 598 1 00 27 43 0

If HETATM 2602 0 HOH 149 -28.236 44.072 -1.540 1.00 27.54 O

HETATM 2603 0 HOH 150 -32 .977 18 .503 2 .458 1 .00 36 .29 O

HETATM 2604 0 HOH 151 -14 .712 48 .441 28 .990 1 .00 31 .59 O

HETATM 2605 0 HOH 152 -6 .222 31 .014 26 .527 1 .00 38 .34 O

HETATM 2606 0 HOH 153 -20 .828 56 .149 27 .115 1 .00 32 .81 O

HETATM 2607 0 HOH 154 -31 .089 55 .843 16 .097 1 .00 26 .16 O

HETATM 2608 0 HOH 155 -36 .042 41 .631 -9 .938 1 .00 37 .68 O

HETATM 2609 0 HOH 156 -36 .271 53 .198 13 .651 1 .00 28 .28 O

HETATM 2610 0 HOH 157 -4 .038 38 .132 14 .671 1 .00 37 .21 O

HETATM 2611 0 HOH 158 -28 .569 27 .068 12 .990 1 .00 33 .87 O

HETATM 2612 0 HOH 159 -4 .412 33 .808 15 .919 1 .00 25 .13 O

HETATM 2613 0 HOH 160 -30 .739 45, .635 29 .049 1, .00 16 .71 0

HETATM 2614 0 HOH 161 -25 .235 59 .875 7 .698 1 .00 37 .03 0

HETATM 2615 0 HOH 162 -13 .187 40 .833 4 .124 1 .00 31 .49 0

HETATM 2616 0 HOH 163 -11, .112 46 .370 27 .075 1, .00 36 .53 0

HETATM 2617 0 HOH 164 -18 .867 52 .128 31 .708 1 .00 31 .14 0

HETATM 2618 0 HOH 165 -15, .707 60 .815 15 .728 1 .00 31 .75 0

HETATM 2619 0 HOH 166 -37, .563 27 .214 17, .479 1, .00 25 .49 0

HETATM 2620 0 HOH 167 -12, .123 26, .276 25, .847 1, .00 31 .14 0

HETATM 2621 0 HOH 168 -17 .609 21 .554 -0 .840 1, .00 24 .08 0

HETATM 2622 0 HOH 169 -21, .028 42 .014 38, .354 1, .00 31 .50 0

HETATM 2623 0 HOH 170 -30, .732 29, .306 12, .288 1, .00 24 .68 0

HETATM 2624 0 HOH 171 -28 .219 42 .432 -3 .693 1, ,00 42 .51 0

HETATM 2625 0 HOH 172 -34, .081 37 .992 -15, .821 1, .00 37 .52 0

HETATM 2626 0 HOH 173 -20, .489 56, .781 21, ,180 1, .00 27 .47 0

HETATM 2627 0 HOH 174 -36, .370 42, .129 0, .935 1. .00 27, .03 0

HETATM 2628 0 HOH 175 -6 .336 27, .826 9, .670 1, .00 41 .60 0

HETATM 2629 0 HOH 176 -18, .621 48, .626 -2, .657 1. .00 23, .43 0

HETATM 2630 0 HOH 177 -38. .790 50, .385 12, .340 1. .00 34, .46 0

HETATM 2631 0 HOH 178 -0 .797 46, .865 19, .558 1, .00 34 .19 0

HETATM 2632 0 HOH 179 -34, .487 40, .143 -2, .895 1. .00 35, .97 0

HETATM 2633 0 HOH 180 -42. .220 32, .053 0, .398 1. .00 38, .27 0

HETATM 2634 0 HOH 181 -14. .051 27. .077 37. ,718 1. .00 38, .53 0

HETATM 2635 0 HOH 182 -15, .620 48, .488 -0. .342 1. .00 30, .30 0

HETATM 2636 0 HOH 183 -10. .245 48, .218 2. .887 1. .00 31, .14 0

HETATM 2637 0 HOH 184 -11. .322 50. .968 3. .775 1. .00 29, .05 0

HETATM 2638 0 HOH 185 -2, .147 39, .295 11, .604 1. .00 22 .50 0

HETATM 2639 0 HOH 186 -0, .803 46, ,473 15. .843 1, .00 30, .41 0

HETATM 2640 0 HOH 187 -54. .476 37. .810 -4. .706 1. ,00 35. .61 0

HETATM 2641 0 HOH 188 -31. ,761 46. .110 18. ,272 1. ,00 31. .97 0

HETATM 2642 0 HOH 189 -37. ,464 48, .671 2. .312 1. .00 31, ,63 0

HETATM 2643 0 HOH 190 -29. .849 48, .597 0. .221 1. ,00 35. .51 0

HETATM 2644 0 HOH 191 -33. ,657 49. ,817 2. ,457 1. ,00 32. .95 0

HETATM 2645 0 HOH 192 -29. ,582 46, .367 -1. ,369 1. ,00 31. .52 0

HETATM 2646 0 HOH 193 -39. ,584 41, .649 22. .374 1. .00 33. .87 0

HETATM 2647 0 HOH 194 -39, ,996 39, .743 25. .222 1. ,00 40. ,68 0

HETATM 2648 0 HOH 195 -26. .489 45. .788 34. .039 1. .00 33. .44 0

HETATM 2649 0 HOH 196 -30. .657 48, .674 28. .851 1, .00 33. .43 0

HETATM 2650 0 HOH 197 -27. ,615 53. .609 33. .744 1. ,00 29, .33 0

HETATM 2651 0 HOH 198 -27. ,813 55. .997 32. ,128 1. ,00 34. ,35 0

HETATM 2652 0 HOH 199 -30. .164 58. .677 12. .725 1. .00 27. .86 0

HETATM 2653 0 HOH 200 -26, ,751 47. .548 -3. ,009 1. ,00 39, ,21 0

HETATM 2654 0 HOH 201 -29. ,858 52. .150 19. ,510 1. ,00 40, ,90 0

HETATM 2655 0 HOH 202 -33. ,820 51. .586 17. ,356 1. .00 41. .26 0

CONECT 1187 1186 2452

CONECT 1286 1284 2452

CONECT 1338 1337 1339 1344 CONECT 1344 1338 1345

CONECT 1345 1344 1346 1348

CONECT 1346 1345 1347 1360

CONECT 1347 1346

CONECT 1348 1345 1349

CONECT 1349 1348 1350 1351

CONECT 1350 1349 1352

CONECT 1351 1349 1353

CONECT 1352 1350 1354

CONECT 1353 1351 1354

CONECT 1354 1352 1353 1355

CONECT 1355 1354 1356

CONECT 1356 1355 1357 1358 1359

CONECT 1357 1356

CONECT 1358 1356

CONECT 1359 1356

CONECT 1360 1346 1361

CONECT 1378 1377 1379 1384

CONECT 1384 1378 1385

CONECT 1385 1384 1386 1388

CONECT 1386 1385 1387 1400

CONECT 1387 1386

CONECT 1388 1385 1389

CONECT 1389 1388 1390 1391

CONECT 1390 1389 1392

CONECT 1391 1389 1393

CONECT 1392 1390 1394

CONECT 1393 1391 1394

CONECT 1394 1392 1393 1395

CONECT 1395 1394 1396

CONECT 1396 1395 1397 1398 1399

CONECT 1397 1396

CONECT 1398 1396

CONECT 1399 1396

CONECT 1400 1386 1401

CONECT 1401 1400 1402 1404

CONECT 1402 1401 1403 1416

CONECT 1403 1402

CONECT 1404 1401 1405

CONECT 1405 1404 1406 1407

CONECT 1406 1405 1408

CONECT 1407 1405 1409

CONECT 1408 1406 1410

CONECT 1409 1407 1410

CONECT 1410 1408 1409 1411

CONECT 1411 1410 1412

CONECT 1412 1411 1413 1414 1415

CONECT 1413 1412

CONECT 1414 1412

CONECT 1415 1412

CONECT 1416 1402 1417

CONECT 2421 2422 2423 2424 2428

CONECT 2422 2421

CONECT 2423 2421 2452

CONECT 2424 2421

CONECT 2425 2426 2427 2428 2432

CONECT 2426 2425 CONECT 2427 2425 2452

CONECT 2428 2421 2425

CONECT 2429 2430 2431 2432 2433

CONECT 2430 2429

CONECT 2431 2429

CONECT 2432 2425 2429

CONECT 2433 2429 2434

CONECT 2434 2433 2435

CONECT 2435 2434 2436 2437

CONECT 2436 2435 2441

CONECT 2437 2435 2438 2439

CONECT 2438 2437

CONECT 2439 2437 2440 2441

CONECT 2440 2439

CONECT 2441 2436 2439 2442

CONECT 2442 2441 2443 2451

CONECT 2443 2442 2444

CONECT 2444 2443 2445

CONECT 2445 2444 2446 2451

CONECT 2446 2445 2447 2448

CONECT 2447 2446

CONECT 2448 2446 2449

CONECT 2449 2448 2450

CONECT 2450 2449 2451

CONECT 2451 2442 2445 2450

CONECT 2452 1187 1286 2423 2427

MASTER 230 0 6 14 13 0 0 6 2653 2 86 26

END

i)

Claims

WE CLALM: 11 ■" V "IF" , " U S lllli 3. ■"" O S !l„ ,!::ilf έl

1. A method for identifying an agent capable of binding to a juxtamembrane-kinase interaction (JKI) site of an insulin receptor, comprising:

(a) contacting the JKI site with an agent to be tested; and

(b) determining if the agent binds the JKI site.

2. The method of claim 1, wherein the JKI site comprises Tyr984, Glu990, Leul045, and Nail 065 in the native conformation of the insulin receptor.

3. The method of claim 2, wherein the JKI site of an insulin receptor is defined by the coordinates of APPENDIX A.

4. The method of claim 1 , wherein the JKI site is part of an insulin receptor, wherein the insulin receptor is a native insulin receptor or functional fragment thereof or a recombinant insulin receptor or functional fragment thereof.

5. The method of claim 4, wherein the JKI site is immobilized on a solid support.

6. The method of claim 1, wherein binding of the agent to the JKI site is determined by virtual ligand screening.

7. The method of claim 1, wherein binding of the agent to the JKI site is determined by in vitro assay.

8. The method of claim 7, wherein the in vitro assay is a cell-free assay or a cell- based assay.

9. The method of claim 1, wherein binding of the agent to the JKI site is determined in vivo.

10. The method of claim 1, wherein the agent is selected from the group consisting of a protein, a peptide, DNA, RNA, carbohydrates, lipids, peptidomimetics, and small molecules.

11. The method of claim 1 , wherein binding of the agent to the JKI site modulates

27 i msulm receptor actii

12. The method of claim 11, wherein the modulation effectuates an increase in insulin receptor activity.

13. The method of claim 11 , wherein the modulation effectuates a decrease in insulin receptor activity.

14. A method for identifying a modulator of insulin receptor activity, comprising:

(a) contacting a juxtamembrane-kinase interaction (JKI) site of an insulin receptor with an agent; and

(b) determining if the agent binds the JKI domain, wherein agent binding to the JKI domain is capable of modulating insulin receptor activity.

15. The method of claim 14, wherein the modulator is selected from the group consisting of a protein, a peptide, DNA, RNA, carbohydrates, lipids, peptidomimetics, and small molecules.

16. The method of claim 14, wherein the modulator of insulin receptor activity is an activator of insulin receptor activity.

17. The method of claim 16, wherein the activator of insulin receptor activity effectuates a decrease in intrinsic inhibition of the insulin receptor.

18. The method of claim 14, wherein the modulator of insulin receptor activity is an inhibitor of insulin receptor activity.

19. An agent identified by the method of any of claims 1 to 18.

20. A pharmaceutical composition comprising an agent of claim 19 and a pharmaceutically acceptable carrier.

21. An agent identified by the method of claim 12.

22. A pharmaceutical composition comprising an agent of claim 21 and a

28 pharmaceutically ad table carrier.

23. A modulator identified by the method of claim 14.

24. A pharmaceutical composition comprising the modulator of claim 23 and a pharmaceutically acceptable carrier.

25. A modulator identified by the method of claim 16.

26. A pharmaceutical composition comprising the modulator of claim 25 and a pharmaceutically acceptable carrier.

27. A method for treating a patient with type II diabetes, comprising administering a pharmaceutical composition of claim 22 to a subject in need thereof.

28. A method for treating a patient with type II diabetes, comprising administering a pharmaceutical composition of claim 26 to a subject in need thereof.

29. The method of claim 12, wherein the agent effectuating an increase in insulin receptor activity is a protein or peptide.

30. A nucleic acid sequence encoding the protein or peptide of claim 29.

31. A method for treating a patient with type II diabetes, comprising administering an expression vector comprising a nucleic acid sequence of claim 30 to a subject in need thereof.

32. The method of claim 16 wherein the activator of insulin receptor activity is a protein or peptide.

33. A nucleic acid sequence encoding the protein or peptide of claim 32.

34. A method for treating a patient with type II diabetes, comprising administering an expression vector comprising a nucleic acid sequence of claim 33 to a subject in need thereof.

35. An antigenic peptide comprising a juxtamembrane-kinase interaction (JKI) site of

29 an insulin receptor, antigenic fragment thereof.

36. An antibody immunologically specific for a juxtamembrane-kinase interaction (JKI) site or a fragment thereof.

37. An antibody of claim 36, wherein antibody binding to the JKI site or a fragment thereof increases tyrosine kinase activity.

38. A method for treating a patient with type II diabetes, comprising administering an antibody of claim 37 to a subject in need thereof.

39. A composition comprising an antibody of claim 37 and a pharmaceutically acceptable carrier.

40. A method for treating a patient with type II diabetes, comprising administering a composition of claim 39 to a subject in need thereof.

41. A method for designing an agent capable of binding to a juxtamembrane-kinase interaction (JKI) site of an insulin receptor, comprising:

(a) designing an agent to fit the JKI binding site;

(b) generating the agent;

(c) contacting the agent with the JKI site; and

(d) determining if the agent binds the JKI site.

42. The method of claim 41, wherein binding of the agent to the JKI is determined by virtual ligand screening.

43. The method of claim 41, wherein the JKI site comprises Tyr984, Glu990, Leul045, and Nail 065 in the native conformation of the insulin receptor.

44. The method of claim 43, wherein the JKI site of an insulin receptor is defined by the coordinates of APPENDIX A.

45. The method claim 11, further comprising testing the agent for binding to a receptor tyrosine kinase, wherein said receptor tyrosine kinase is vascular endothelial growth

30 ffi factor receptor-2 or oblast growth factor receptor-l_?jcomprising>

(a) contacting the receptor tyrosine kinase with the agem , m

(b) determining if the agent binds the receptor tyrosine kinase.

46. The method of claim 45, further comprising determining an ability of the agent to modulate activity of the receptor tyrosine kinase.

47. The method claim 14, further comprising testing the agent for binding to a receptor tyrosine kinase, wherein said receptor tyrosine kinase is vascular endothelial growth factor receptor-2 or fibroblast growth factor receptor- 1, comprising:

(a) contacting the receptor tyrosine kinase with the agent ; and

(b) determining if the agent binds the receptor tyrosine kinase.

48. The method of claim 47, further comprising determining an ability of the agent to modulate activity of the receptor tyrosine kinase.

49. The method claim 41 , further comprising testing the agent for binding to a receptor tyrosine kinase, wherein said receptor tyrosine kinase is vascular endothelial growth factor receptor-2 or fibroblast growth factor receptor- 1, comprising:

(a) contacting the receptor tyrosine kinase with the agent ; and

(b) determining if the agent binds the receptor tyrosine kinase.

50. The method of claim 49, further comprising determimng an ability of the agent to modulate activity of the receptor tyrosine kinase.

51. A kit including at least one container comprising at least one pharmaceutical composition claim 20 and an instruction manual.

52. A kit including at least one container comprising at least one pharmaceutical composition claim 22 and an instruction manual.

53. A kit including at least one container comprising at least one pharmaceutical composition claim 24 and an instruction manual.

54. A kit including at least one container comprising at least one pharmaceutical

³¹ & composition claim 2 id an instruction manual. , , „ , .„., „ „„„ „,,, „„ ,,„.„ „„,, C ^' ii^'" U iSTI JI J ..^•'^' U «:::!: .1 ^!l s» id!

55. A kit including at least one container comprising at least one pharmaceutical composition claim 39 and an instruction manual.

56. Use of an agent of claim 21 for the treatment of type II diabetes.

57. Use of a modulator of claim 25 for the treatment of type II diabetes.

58. Use of a nucleic acid sequence of claim 30 for the treatment of type II diabetes.

59. Use of a nucleic acid sequence of claim 33 for the treatment of type II diabetes.

60. Use of an antibody of claim 37 for the treatment of type II diabetes.

61. Use of a composition of claim 39 for the treatment of type II diabetes.

62. The method of claim 50, wherein said ability of an agent to modulate activity of a receptor tyrosine kinase effectuates an increase in the activity of the receptor tyrosine kinase.

63. An agent identified by the method of claim 62.

64. Use of an agent of claim 63 for the treatment of wounds and/or to promote vascularization.

65. Use of an agent as claimed in claim 64 wherein said vascularization is promoted in transplanted organs or grafts.

66. The method of claim 50, wherein said ability of an agent to modulate activity of a receptor tyrosine kinase effectuates a decrease in the activity of the receptor tyrosine kinase.

67. An agent identified by the method of claim 66.

68. Use of an agent of claim 67 for the treatment of cancer and/or to inhibit tumor angiogenesis.

69. The method of claim 66, wherein the receptor tyrosine kinase is fibroblast growth factor receptor- 1.

70. An agent identified by the method of claim 69.

71. Use of an agent of claim 70 for the treatment of a craniofacial disorder.

72. Use of an agent as claimed in claim 71 , wherein said craniofacial disorder is Crouzon Syndrome or Apert Syndrome.

33 ?