WO2005028507A1

WO2005028507A1 - CRYSTAL STRUCTURE OF CD3ϵϜ/OKT3 COMPLEX

Info

Publication number: WO2005028507A1
Application number: PCT/AU2004/001323
Authority: WO
Inventors: Jamie Rossjohn; Travis Beddoe; Michelle Dunstone; Lauren Ely; James Mccluskey; Lars Kjer-Nielsen; Lyudmila Kostenko; Anthony Purcell
Original assignee: University of Melbourne; Monash University
Current assignee: University of Melbourne; Monash University
Priority date: 2003-09-24
Filing date: 2004-09-24
Publication date: 2005-03-31
Anticipated expiration: 2006-03-24

Abstract

The present invention provides the crystal structure of CD3ϵϜ in complex with the monoclonal antibody OKT3. This allows for the determination of the binding domains of these moieties. This allows rational drug design to be carried out on the basis of this information.

Description

CRYSTAL STRUCTURE OF CD3εγ / OKT3 COMPLEX FIELD OF THE INVENTION There is an ever increasing need to design and/or identify agents for the treatment of medical conditions of clinical interest. In many cases the active agent works by targeting a receptor site in the human or animal body that serves to mediate the effects of the condition. The present invention relates to methods for identifying and/or designing agents that may find use in therapeutic applications such as in the treatment of transplant rejection and autoimmune disease. BACKGROUND OF THE INVENTION The T-cell antigen receptor is a critical and complex component of the immune system. Central to the T-cell mediated recognition event within the immunological synapse is the interaction between the clonotypic αβ T-cell receptor (TcR) and the peptide- laden major histocompatibility complex (pMHC). From recent structural studies, some of the basic principles underlying the TcR/pMHC interaction have been gleaned. The emerging paradigm suggests a common diagonal docking mode, whereby the complementarity determining loops, CDR1 and CDR2, contact the MHC α-helices of the antigen-binding groove, whilst the more diverse CDR3 α and β loops interact primarily with the peptide. Whilst deviations from this generality have been observed, the conserved diagonal-docking mode within class I complexes is considered to be important in mediating co-receptor binding. However, how this TcR/pMHC recognition event leads to co-receptor binding is unresolved. Moreover, the mechanism by which TcR ligation is directly communicated to the signalling apparatus remains a fundamental question in T cell biology. The signalling apparatus of the TcR is the multi-component complex, CD3, which comprises the ε, γ, δ and ζ subunits. These subunits associate with each other to form a CD3εγ heterodimer, a CD3εδ heterodimer and a CD3ζζ homodimer. Gene-knockout studies have revealed that the CD3 molecules not only play a critical role in T-cell signalling, but also are required for the cell surface expression of the αβ TcR. The extracellular domains of the ε, γ and δ subunits adopt an immunoglobulin (Ig)-type topology, a cysteine-rich stalk, a trans-membrane region, and a cytoplasmic domain that contains the immuno-receptor tyrosine-based activation motifs. Located within the transmembrane regions of the αβ TcR and the CD3 components are charged residues that appear to dictate the stoichiometry of the TcR/CD3 complex, namely one αβ TcR binds to one CD3εγ heterodimer, one CD3εδ heterodimer and one CD3ζζ homodimer. Although these essential CD3 components are found throughout the animal kingdom, the sequence identities within the subunits is surprisingly low, which may suggest difference in the mode of TcR ligation. Recently, the solution structure of the ectodomain fragment of the CD3εγ heterodimer from mouse has been reported, with each subunit comprising a C2-set Ig domain that interact with each other to form an unusual side-to-side dimer-configuration. This rigid pairing of the subunits is considered to favour a piston-like mechanism T-cell signalling. However, a recent study reports that TcR/CD3 ligation induces a conformational change that leads to the recruitment of an adaptor protein, Nek, to the human CD3ε cytoplasmic tail. In support of this, there is one report that describes a conformational change in the constant domain of the TcR upon HLA ligation. Given the significance of the CD3 receptor in T cell activity a number of approaches have been developed with the view of targeting this receptor an thus mediating receptor signalling. Therapeutic strategies developed to modulate events central to the adaptive immune response have met with certain degrees of success. One such class of therapeutics are the anti-human CD3 monoclonal antibodies that have been widely used in a variety of settings, ranging from useful tools for dissecting CD3 function to clinically- proven therapeutics. One such antibody, the mouse monoclonal OKT3, can be considered the prototype of the class of anti-CD3 monoclonal antibodies. Since OKT3's development in 1979, it has been used widely in clinical practise as a non-specific immunosuppressant in transplantation. Most recently, a humanized version of OKT3 has been used for the treatment of autoimmune diseases. Although the mode of action of OKT3 is mutli-faceted, it involves the specific interaction with the CD3ε component. A comprehensive review of the use of CD3 specific antibodies of this type can be found in the review article of Chatenoud entitled "CD3 Specific Antibody Induced Active Tolerance: From Bench to Bedside" in nature Volume 3, February 2003 pp 123-132. It is apparent therefore that the design of ligands that target the same active site on CD3 as the OKT3 ligand would be expected to have useful activity in mediating the T cell signalling and hence would be useful in the treatment of transplant rejection and in autoimmune disease. Indeed the success that has been achieved with the development of second generation monoclonal antibodies that mimic the behaviour of OKT3 bears this out. These molecules are attractive in drug development applications as OKT3 is found to successfully suppress the immune system whilst in the bloodstream but following termination of treatment with the monoclonal antibody the immune system is observed to recover to full operation in a relatively short period of time. This is highly suggestive that the drug acts as a reversible inhibitor of immune function. It would therefore clearly be desirable to be able to generate alternatives to the use of OKT3 or its successors in therapeutic applications. It would therefore be desirable to determine the crystal structure of the binding domain of CD3 in complex with the known ligands in order facilitate the identification and development of ligands of the domain that could be used to mediate the activity of the receptor in humans and other species. There has thus been a significant amount of effort put in place to design active agents such as ligands that target the extracellular portion of the receptor thus interfering with normal signalling. In the past the development of synthetic or biosynthetic ligands that specifically bind to a given receptor has largely been carried out by the trial and error method of drug design with a multitude of possible candidates being screened for the desired activity. As such in drug design new ligands for the receptor of interest were typically discovered in the absence of informat ion on the three dimensional structure of the receptor with a bound ligand. hi more recent times computer modelling programs have been developed that could be provided with information on the extracellular Domain of the receptor and the program would attempt to develop a model for the receptor on the basis of thermodynamic assumptions. Whilst these approaches have met with more success than the trial and error approach they still involve significant leaps of faith that are unjustified in many instances. In essence in designing ligands for the CD3 receptor prior to the present invention researchers were essentially discovering ligands by probing essentially blindly and without the ability to accurately visualise how the amino acids of the receptor in question bound to the ligand. As a result of the well appreciated relationship between the use of monoclonal antibodies and the CD3 receptor the authors targeted the receptor complex as a potential source of information in the development of potential therapeutics. There are many difficulties with the use of monoclonal antibodies in clinical applications and it was hoped that the structural studies would provide information that would allow the development and or design of therapeutic agents that retained the crucial activity whilst at the same time alleviating some of the inherent difficulties observed with the use of monoclonal antibodies. For example it would be anticipated that a therapeutic could be designed that retained the activity whilst at the same time overcame many of the difficulties associated wit the delivery of the monoclonal antibody to the patient. It would therefore be desirable to be able to design alternative ligands that targeted the CD3 receptor that could potentially be used as therapeutic agents clinically in place of the monoclonal antibodies developed so far. Structural details of the binding domain of the CD3 receptor have not been provided previously nor have any structures of this receptor in complex with a receptor ligand been reported. The present applicants have determined the crystal structure of the extracellular domain of the receptor in complex with the known ligand OKT3. The crystal structure data of the extracellular domain of the receptor in complex with the known ligand has allowed the amino acid residues (and portions thereof) crucial for binding to be determined which will allow for the rational design of ligands that may be used in treatments aimed at preventing conditions in which the receptor is implicated. At least in theory as the receptor is known to be involved in T-cell signalling the ligands should find application in any situation in which suppression of the immune system is desirable. One example of where suppression of the immune system is desirable is in the prophylaxis and treatment of transplant rejection such as liver, heart and kidney transplant rejection and autoimmune diseases. A non limiting list of autoimmune diseases in which the ligands may be useful would include Multiple sclerosis, Myasthenia gravis, Guillain-Barre, Autoimmune uveitis, Crohn's Disease, Ulcerative colitis, Primary Bilary cirrhosis, Autoimmune hepatitis Autoimmune hemolytic anemia, Pernicious anemia, Autoimmune thrombocytopenia, immune mediated diabetes mellitus, Grave's Disease, Hashimoto's thyroiditis, Autoimmune oophoritis and orchitis, Autoimmune disease of the adrenal gland, Temporal arteritis, Anti-phospholipid syndrome, Vasculitides such as Wegener's granulomatosis, Behcet's disease, Rheumatoid arthritis, Systemic lupus erythematosus, Psoriasis, Scleroderma, Dermatitis herpetiformis, Polymyositis, dermatomyositis, Pemphigus vulgaris, Spondyloarthropathies such as ankylosing spondylitis, Sjogren's syndrome and Vitiligo. Accordingly, there is a need to determine the binding domain of the CD3 receptor in order to enable the information to be used in rational drug design. SUMMARY OF THE INVENTION The applicants have determined the crystal structure of a binding domain of CD3 in complex with a known ligand (OKT3 Fab fragment) at a resolution of 2.1 angstrom. The present invention provides for the first time crystals of the binding domain of the CD3 receptor with a ligand (OKT3 Fab fragment) bound to the ligand binding domain. In one aspect, the present invention provides a crystal of the extracellular domain of the CD3 receptor in complex with the OKT3 monoclonal antibody or a derivative thereof (Fab Fragment). In a preferred embodiment the crystal is of the CD3εγ heterodimer in complex with a Fab fragment of OKT3. It is particularly preferred that the CD3εγ is human CD3εγ. It is preferred that the crystal provided has the orthorhombic space group symmetry F2_\. h a particularly preferred embodiment the crystal has unit cell dimensions a= 67.7, b = 55.5, c = 96.05 angstroms. In this preferred embodiment, the crystal preferably has angles α=90°, β=100.85°, γ=90°. In a preferred embodiment the crystal has the orthorhombic space group symmetry P2₁2₁2₁. The crystal preferably has atoms arranged in the spatial relationship represented by the structure coordinates listed in figure 5. The analysis of the three dimensional structure of the crystal provides previously unknown 3 dimensional information about the binding domain and should be useful in designing potential drug candidates. In yet further embodiments there is provided models (both partial and complete) for the structure of the CD3εγ heterodimer including a data set embodying at least a portion of the structure of the CD3εγ. hi preferred models the model includes the binding domain of CD3εγ. In yet further embodiments there is provided models (both partial and complete) for the structure of the OKT3 monoclonal antibody including a data set embodying at least a portion of the structure of the OKT3. In preferred models the model includes the CD3εγ recognising binding domain of OKT3. The models of the invention may be constructed using any of the known available methods from the crystallographic data detailed herein. For example such a model can be constructed from the provided crystallographic data using known software packages such as BUSTER, CHAIN, CCP4, DIANA, FELIX, FRODO, HKL, HEAVY, MADIGRAS, MOSFJXM, PHASES, O, RASMOL, SHARP, SOLVE, XDS and XPLOR merely to name a few. In yet a further aspect the invention provides a binding domain or portion thereof of the CD3εγ heterodimer. In one preferred embodiment the binding domain includes at least one amino acid selected from the group consisting of: Thr 12, Pro 13, Lys 15, Ser 17, Ser 19, Gly 20, Thr 21, Thr 22, He 24, Thr 26, Gln 29, Pro 31, Ser 33, Glu 34, Asn 40, Asp 41, Lys 42, Asn 43, Asp 47, Glu 48, Asp 49, Asp 50, Lys 51, Asn 52, Asp 56, Glu 57, Asp 58, His 59, Ser 61, Lys 63, Glu 64, Ser 66, Glu 67, Leu 68, Glu 69, Arg 79, Lys 82, Pro 83, Glu 84, Asp 85, Asn 87, Arg 95 of the epsilon chain of the CD3εγ or an equivalent amino acid residue. A particularly preferred domain within this domain includes at least one amino acid selected from the group consisting of Glu 48, Asp 49, Asp 56, Glu 57, Asp 58, Glu 64, Glu 69 of the epsilon chain of CD3εγ or an equivalent amino acid residue. In a further preferred embodiment the binding domain includes at least one amino acid selected from the group consisting of: Gln 1, Ser 2, Lys 4, Asn 6, Tyr 12, Asp 13, Ala 14, Glu 16, Asp 17, Thr 23, Asp 25, Glu 27, Ala 28, Lys 29, Asp 36, Lys 38, Thr 44, Glu 45, Asp 46, Lys 47, Lys 48, Lys 49, Asn 51, Ser 54, Ala 56, Lys 57, Asp 58, Arg 60, Lys 66, Ser 68, Gln 69, Asn 70, Lys 71, Lys 73, Arg 80 of the gamma chain of CD3εγ or an equivalent amino acid residue. A particularly preferred subset of this binding domain includes at least one amino acid selected from the group consisting of Lys 35, Lys 38, Lys 57, Arg 60, Lys 66, Lys 71, Lys 73 of the gamma chain of CD3εγ or an equivalent amino acid residue. h another preferred embodiment the binding domain includes at least one amino acid residue selected from the group consisting of Glu34, Gly46, Glu48, Arg79, Gly80, Ser81, Lys82, Pro83, Asp 85 of the epsilon chain of CD3εγ or an equivalent amino acid residue. In a particularly preferred embodiment the amino acid residues in each of the binding domains are in the same relative spatial configuration as the corresponding amino acid residues in figure 5. hi yet a further aspect the invention provides the binding domain or portion thereof of the OKT3 monoclonal antibody that recognises the CD3 receptor, hi a preferred embodiment the binding domain includes at least one amino acid residue selected from the group consisting of: Ser30, Tyr 31, Asp 49, Trp90, and Ser91 of the light chain and Thr33, Tyr50, Asn52, Arg55, Tyr57, Lys74, Tyr99, AsplOl and Tyrl04 of the heavy chain of the OKT3 or an equivalent amino acid residue, h a particularly preferred embodiment the amino acid residues in the binding domain are in the same relative spatial configuration as the corresponding amino acid residues in figure 5. In a most preferred embodiment the binding domain of the OKT3 is defined by the atoms listed for the relevant amino acid residues as shown in table 1. In yet a further aspect the invention provides a molecule or molecular complex wherein at least a portion of the structural coordinates of the molecule or molecular complex define the same relative spatial configuration as at least a portion of the structural coordinates of the CD3εγ receptor as set out in figure 5. In one preferred embodiment at least a portion of the coordinates of the molecule or molecular complex define the same relative spatial configuration as at least a portion of the coordinates of the binding domain defined by amino acid residues Thr 12, Pro 13, Lys 15, Ser 17, Ser 19, Gly 20, Thr 21, Thr 22, He 24, Thr 26, Gln 29, Pro 31, Ser 33, Glu 34, Asn 40, Asp 41, Lys 42, Asn 43, Asp 47, Glu 48, Asp 49, Asp 50, Lys 51, Asn 52, Asp 56, Glu 57, Asp 58, His 59, Ser 61, Lys 63, Glu 64, Ser 66, Glu 67, Leu 68, Glu 69, Arg 79, Lys 82, Pro 83, Glu 84, Asp 85, Asn 87, Arg 95 of the epsilon chain of CD3εγ. A particularly preferred molecule or molecular complex is one in which at least a portion of the coordinates of the molecule or molecular complex define the same relative spatial configuration as at least a portion of the coordinates of a binding domain defined by amino acid residues Glu 48, Asp 49, Asp 56, Glu 57, Asp 58, Glu 64, Glu 69 of the epsilon chain of CD3εγ. In a most preferred embodiment the molecule or molecular complex has coordinates that define the same relative spatial configuration as all the amino acid residues in this domain. hi another preferred embodiment at least a portion of the coordinates of the molecule or molecular complex define the same relative spatial configuration as at least a portion of the coordinates of the binding domain defined by amino acid residues Gln 1, Ser 2, Lys 4, Asn 6, Tyr 12, Asp 13, Ala 14, Glu 16, Asp 17, Thr 23, Asp 25, Glu 27, Ala 28, Lys 29, Asp 36, Lys 38, Thr 44, Glu 45, Asp 46, Lys 47, Lys 48, Lys 49, Asn 51, Ser 54, Ala 56, Lys 57, Asp 58, Arg 60, Lys 66, Ser 68, Gln 69, Asn 70, Lys 71, Lys 73, Arg 80 of the gamma chain of CD3εγ. A particularly preferred molecule or molecular complex is one in which at least a portion of the coordinates of the molecule or molecular complex define the same relative spatial configuration as at least a portion of the coordinates of a binding domain defined by amino acid residues Lys 35, Lys 38, Lys 57, Arg 60, Lys 66, Lys 71, Lys 73 of the gamma chain of CD3εγ. In a most preferred embodiment the molecule or molecular complex has coordinates that define the same relative spatial configuration as all the amino acid residues in this domain. hi another preferred embodiment at least a portion of the structural coordinates of the molecule or molecular complex define the same relative spatial configuration as at least a portion of the coordinates of residues Glu 34, Gly 46, Glu 48, Arg 79, Gly 80, Ser 81, Lys 82, Pro 83, Asp 85 of the epsilon chain of CD3εγ. It is particularly preferred that at least a portion of the coordinates of the molecule or molecular complex define the same relative spatial configuration as a plurality of these amino acid residues. In a most preferred embodiment at least a portion of the structure coordinates of the molecule or molecular complex define the same relative spatial configuration as the coordinates of Glu34, Gly46, Glu48, Arg79, Gly80, Serδl, Lys82, Pro83, Asp 85 of the epsilon chain of CD3εγ. hi another preferred embodiment at least a portion of the structural coordinates of the molecule or molecular complex define the same relative spatial configuration as at least a portion of the structure coordinates of the atoms of the CD3ε chain identified in table 1 as being involved in binding of the CD3εγ to OKT3. In yet a further aspect the invention provides a molecule or molecular complex wherein at least a portion of the structural coordinates of the molecule or molecular complex define the same relative spatial configuration as at least a portion of the structure coordinates of OKT3 in figure 5. In a preferred embodiment at least a portion of the structural coordinates of the molecule or molecular complex define the same relative spatial configuration as at least a portion of the coordinates of residues : Ser30, Tyr 31, Asp 49, Trp90, and Ser91 of the light chain and Thr33, Tyr50, Asn52, Arg55, Tyr57, Lys74, Tyr99, AsplOl and Tyr 104 of the heavy chain of the OKT3 as set out in figure 5. In a most preferred embodiment at least a portion of the structure coordinates of the molecule or molecular complex define the same relative spatial configuration as the coordinates of a plurality of residues selected from the group consisting of : Ser30, Tyr 31, Asp 49, Trp90, and Ser91 of the light chain and Thr33, Tyr50, Asn52, Arg55, Tyr57, Lys74, Tyr99, AsplOl and Tyrl04 of the heavy chain of the OKT3 as set out in figure 5. In another preferred embodiment at least a portion of the structural coordinates of the molecule or molecular complex define the same relative spatial configuration as at least a portion of the structure coordinates of the atoms of the OKT3 light and heavy chain identified in table 1 as being involved in binding of the OKT3 to CD3ε. In an even further aspect the invention provides a data set defining a scalable three dimensional configuration of points at least a portion of the data set being derived from, or defining the same relative spatial configuration as, at least a portion of the structure coordinates of a CD3/OKT3 complex. In a preferred embodiment at least a portion of the data is derived from or defines the same relative spatial configuration as at least a portion of the structure coordinates of a crystalline CD3/OKT3 complex in figure 5. In one preferred embodiment at least a portion of the data in the data set is derived from or defines the same relative spatial configuration as at least a portion of the structural coordinates for amino acid residues Thr 12, Pro 13, Lys 15, Ser 17, Ser 19, Gly 20, Thr 21, Thr 22, He 24, Thr 26, Gln 29, Pro 31, Ser 33, Glu 34, Asn 40, Asp 41, Lys 42, Asn 43, Asp 47, Glu 48, Asp 49, Asp 50, Lys 51, Asn 52, Asp 56, Glu 57, Asp 58, His 59, Ser 61, Lys 63, Glu 64, Ser 66, Glu 67, Leu 68, Glu 69, Arg 79, Lys 82, Pro 83, Glu 84, Asp 85, Asn 87, Arg 95 of the epsilon chain of CD3εγ. In another preferred embodiment at least a portion of the data in the data set is derived from or defines the same relative spatial configuration as at least a portion of the structural coordinates for amino acid residues Glu 48, Asp 49, Asp 56, Glu 57, Asp 58, Glu 64, Glu 69 of the epsilon chain of CD3εγ. In another preferred embodiment at least a portion of the data in the data set is derived from or defines the same relative spatial configuration as at least a portion of the structural coordinates for amino acid residues Glu34, Gly46, Glu48, Arg79, Gly80, Ser81, Lys82, Pro83, Asp 85 of the epsilon chain of CD3εγ. In a more preferred embodiment the data set includes data which is derived from or defines the same relative spatial configuration as a plurality of these amino acid residues, preferably all these amino acid residues, hi another preferred embodiment at least a portion of the data set is derived from or defines the same relative spatial configuration as at least a portion of the structure coordinates of the atoms of the CD3ε chain identified in table 1 as being involved in binding of the CD3εγ to OKT3. In one preferred embodiment at least a portion of the data in the data set is derived from or defines the same relative spatial configuration as at least a portion of the structural coordinates for amino acid residues Gln 1, Ser 2, Lys 4, Asn 6, Tyr 12, Asp 13, Ala 14, Glu 16, Asp 17, Thr 23, Asp 25, Glu 27, Ala 28, Lys 29, Asp 36, Lys 38, Thr 44, Glu 45, Asp 46, Lys 47, Lys 48, Lys 49, Asn 51, Ser 54, Ala 56, Lys 57, Asp 58, Arg 60, Lys 66, Ser 68, Gln 69, Asn 70, Lys 71, Lys 73, Arg 80 of the gamma chain of CD3εγ. In another preferred embodiment at least a portion of the data in the data set is derived from or defines the same relative spatial configuration as at least a portion of the structural coordinates for amino acids residues Lys 35, Lys 38, Lys 57, Arg 60, Lys 66, Lys 71, Lys 73 of the gamma chain of CD3εγ. In another preferred embodiment at least a portion of the data in the data set is derived from or defines the same relative spatial configuration as at least a portion of the coordinates of Ser30, Tyr 31, Asp 49, Trp90, and Ser91 of the light chain and Thr33, Tyr50, Asn52, Arg55, Tyr57, Lys74, Tyr99, AsplOl and Tyrl04 of the heavy chain of the OKT3 in figure 5. In a more preferred embodiment the data set includes data derived from or defining the same relative spatial configuration as the coordinates of a plurality of these amino acid residues, preferably all of these amino acid residues. In another preferred embodiment at least a portion of the structural coordinates of the data set are derived from or define the same relative spatial configuration as at least a portion of the structure coordinates of the atoms of the OKT3 light and heavy chain identified in table 1 as being involved in binding of the OKT3 to CD3ε. In an even further aspect the invention provides a scalable three dimensional configuration of points, at least a portion of the points being derived from, or defining the same relative spatial configuration as, at least a portion of the structure coordinates of a CD3/OKT3 complex. In a preferred embodiment at least a portion of points are derived from or defines the same relative spatial configuration as at least a portion of the structure coordinates of a crystalline CD3/OKT3 complex as set out in figure 5. In one preferred embodiment at least a portion of the points is derived from or defines the same relative spatial configuration as at least a portion of the structural coordinates of amino acid residues Thr 12, Pro 13, Lys 15, Ser 17, Ser 19, Gly 20, Thr 21, Thr 22, He 24, Thr 26, Gln 29, Pro 31, Ser 33, Glu 34, Asn 40, Asp 41, Lys 42, Asn 43, Asp 47, Glu 48, Asp 49, Asp 50, Lys 51, Asn 52, Asp 56, Glu 57, Asp 58, His 59, Ser 61, Lys 63, Glu 64, Ser 66, Glu 67, Leu 68, Glu 69, Arg 79, Lys 82, Pro 83, Glu 84, Asp 85, Asn 87, Arg 95 of the epsilon chain of CD3εγ. In another preferred embodiment at least a portion of the points is derived from or defines the same relative spatial configuration as at least a portion of the structural coordinates for amino acids Glu 48, Asp 49, Asp 56, Glu 57, Asp 58, Glu 64, Glu 69 of the epsilon chain of CD3εγ. hi another preferred embodiment at least a portion of the points are derived from or defines the same relative spatial configuration as at least a portion of the structural coordinates for amino acids Glu34, Gly46,. Glu48, Arg79, Gly80, Ser81, Lys82, Pro83, Asp 85 of CD3εγ as set out in figure 5. In a more preferred embodiment the set of points includes points which are derived from or defines the same relative spatial configuration as a plurality of these amino acid residues, preferably all these amino acid residues. In another preferred embodiment at least a portion of the points are derived from or define the same relative spatial configuration as at least a portion of the structure coordinates of the atoms of the CD3ε chain identified in table 1 as being involved in binding of the CD3εγ to OKT3. In another preferred embodiment at least a portion of the points are derived from or defines the same relative spatial configuration as at least a portion of the structural coordinates for amino acid residues Gln 1, Ser 2, Lys 4, Asn 6, Tyr 12, Asp 13, Ala 14, Glu 16, Asp 17, Thr 23, Asp 25, Glu 27, Ala 28, Lys 29, Asp 36, Lys 38, Thr 44, Glu 45, Asp 46, Lys 47, Lys 48, Lys 49, Asn 51, Ser 54, Ala 56, Lys 57, Asp 58, Arg 60, Lys 66, Ser 68, Gln 69, Asn 70, Lys 71, Lys 73, Arg 80 of the gamma chain of CD3εγ. In another preferred embodiment at least a portion of the points are derived from or defines the same relative spatial configuration as at least a portion of the structural coordinates for amino acids residues Lys 35, Lys 3δ, Lys 57, Arg 60, Lys 66, Lys 71, Lys 73 of the gamma chain ofCD3εγ. In yet another preferred embodiment at least a portion of the points is derived from or defines the same relative spatial configuration as the coordinates of Ser30, Tyr 31, Asp 49, Trρ90, and Ser91 of the light chain and Thr33, Tyr50, Asn52, Arg55, Tyr57, Lys74, Tyr99, AsplOl and Tyrl04 of the heavy chain of the OKT3 as set out in figure 5. In a further aspect of the invention there is provided a method of using the data generated to identify and/or design ligands that are capable of binding to the CD3 binding domain and hence have the potential to act as agonists or antagonists of the receptor. There are a number of ways in which the data can be examined in order to determine potential ligands. These methods typically involve the study of the interaction of the potential ligand candidates (either sourced from a compound library, designed by modification of a compound sourced from a library or designed de novo) with a model of the receptor which includes at least a portion of the binding domain, preferably all of the binding domain. There are a number of software programs that may be utilised in the analysis of these interactions and a non-limiting list includes CAVEAT, CHARM, CHAIN, CATALYST, DOCK, FRODO, INSIGHT, ISIS, LEAPFROG, MODELLER, MCSS/HOOK, O, QUANTUM and RASMOL to name but a few. The present invention therefore also provides a method of an agent which is capable of acting as a ligand of CD3εγ the method including the step of identifying an agent that has a conformation and/or polarity such that it is capable of interacting with at least one relevant amino acid residue or portion thereof of the CD3εγ. In a preferred embodiment the method includes the step of identifying an agent that has a conformation and/or polarity such that it is capable of interacting with one or more amino acid residues selected from the group consisting of: Thr 12, Pro 13, Lys 15, Ser 17, Ser 19, Gly 20, Thr 21, Thr 22, He 24, Thr 26, Gln 29, Pro 31, Ser 33, Glu 34, Asn 40, Asp 41, Lys 42, Asn 43, Asp 47, Glu 4δ, Asp 49, Asp 50, Lys 51, Asn 52, Asp 56, Glu 57, Asp 5δ, His 59, Ser 61, Lys 63, Glu 64, Ser 66, Glu 67, Leu 68, Glu 69, Arg 79, Lys δ2, Pro δ3, Glu δ4, Asp 85, Asn 87, Arg 95 of the epsilon chain of CD3εγ. In another preferred embodiment the method includes the step of identifying an agent that has a conformation and/or polarity such that it is capable of interacting with one or more amino acid residues selected from the group consisting of amino acids Glu 48, Asp 49, Asp 56, Glu 57, Asp 58, Glu 64, Glu 69 of the epsilon chain of CD3εγ. h another preferred embodiment the method includes the step of identifying an agent that has a conformation and/or polarity such that it is capable of interacting with one or more amino acid residues selected from the group consisting of amino acids Glu34, Gly46, Glu48, Arg79, Gly80, Serδl, Lysδ2, Proδ3, Asp 85 of the epsilon chain of CD3εγ. In a more preferred embodiment the agent is capable of interacting with a plurality of these amino acid residues, preferably all these amino acid residues. In another preferred embodiment the method includes the step of identifying an agent that has a conformation and/or polarity such that it is capable of interacting with one or more of the atoms of the CD3ε chain identified in table 1 as being involved in binding ofthe CD3εγ to OKT3. In another preferred embodiment the method includes the step of identifying an agent that has a conformation and/or polarity such that it is capable of interacting with one or more amino acid residues selected from the group consisting Gln 1, Ser 2, Lys 4, Asn 6, Tyr 12, Asp 13, Ala 14, Glu 16, Asp 17, Thr 23, Asp 25, Glu 27, Ala 28, Lys 29, Asp 36, Lys 38, Thr 44, Glu 45, Asp 46, Lys 47, Lys 48, Lys 49, Asn 51, Ser 54, Ala 56, Lys 57, Asp 58, Arg 60, Lys 66, Ser 6δ, Gln 69, Asn 70, Lys 71, Lys 73, Arg δO of the gamma chain of CD3εγ. hi another preferred embodiment the method includes the step of identifying an agent that has a conformation and/or polarity such that it is capable of interacting with one or more amino acid residues selected from the group consisting of Lys 35, Lys 3δ, Lys 57, Arg 60, Lys 66, Lys 71, Lys 73 of the gamma chain of CD3εγ. Of course the method can be carried out in a number of ways such as by hand held modelling and manual transcription techniques (such as depicting the model on a blackboard, for example. It is preferred that the method involves computer assisted modelling. In yet a further aspect there is provided a computer-assisted method for identifying an agent capable of binding to the binding domain of a CD3εγ including the steps of:

(a) supplying a computer modelling application with a set of structure coordinates of a molecule or molecular complex, at least a portion of the structural coordinates of the molecule or molecular complex being derived from, or defining the same relative spatial configuration as, at least a portion of the atomic coordinates of a CD3εγ binding domain as set out in figure 5

(b) supplying the computer modelling application with a set of structure coordinates of an agent; and (c) determining whether the agent is expected to bind to the molecule or molecular complex, wherein binding to the molecule or molecular complex is indicative of binding to the CD3εγ. The step of supplying the computer with a set of structure coordinates of an agent typically involves provision of the coordinates from a chemical library of compounds, hi a particularly preferred embodiment the agent thus identified is then screened using a biological assay to determine if the agent binds to the CD3εγ in vivo and /or in vitro. In yet an even further aspect there is provided a computer-assisted method for designing an agent capable of binding to the binding domain of a CD3εγ including the steps of:

(b) supplying the computer modelling application with a set of structure coordinates for an agent;

(c) evaluating the potential binding interactions between the agent and substrate binding pocket of the molecule or molecular complex; (d) structurally modifying the agent to yield a set of structure coordinates for a modified agent; and (e) determining whether the modified agent is expected to bind to the molecule or molecular complex, wherein binding to the molecule or molecular complex is indicative of a potential ligand of CD3εγ. In a particularly preferred embodiment the agent thus designed is then screened using a biological assay to determine if the agent binds to the CD3εγ in vivo and /or in vitro. In yet an even further aspect the invention provides a computer-assisted method for designing an agent capable of binding to a CD3εγ including:

(a) supplying a computer modelling application with a set of structure coordinates of a molecule or molecular complex, at least a portion of the structural coordinates of the molecule or molecular complex being derived from, or defining the same relative spatial configuration as, at least a portion of the atomic coordinates of the CD3εγ binding domain as set out in figure 5

(b) computationally building a model of an agent represented by set of structure coordinates; and

(c) determining whether the agent is expected to bind to the molecule or molecular complex, wherein binding to the molecule or molecular complex is indicative of potential binding to the CD3εγ. hi a particularly preferred embodiment agent thus designed is then screened using a biological assay to determine if the compound binds to the CD3εγ in vivo and /or in vitro, hi each of these methods a number of possible binding domains can be utilised in step (a). The preferred binding domains are those described above. In yet a further aspect there is provided a computer-assisted method for identifying an agent capable of binding to the binding domain of a CD3εγ including the steps of:

(a) supplying a computer modelling application with a set of structure coordinates of a molecule or molecular complex, at least a portion of the structural coordinates of the molecule or molecular complex being derived from, or defining the same relative spatial configuration as, at least a portion of the atomic coordinates corresponding to Ser30, Tyr 31, Asp 49, Trp90, and Ser91 of the light chain and Thr33, Tyr50, Asn52, Arg55, Tyr57, Lys74, Tyr99, AsplOl and Tyrl04 of the heavy chain of the OKT3 as set out in figure 5.

(b) supplying the computer modelling application with a set of structure coordinates of an agent; and (c) computationally determining the structural similarity of the agent with the molecule or molecular complex, wherein a high level of structural similarity of the agent with the molecule or molecular complex is indicative of potential binding to the CD3εγ. In yet an even further aspect there is provided a computer-assisted method for designing an agent capable of binding to CD3εγ including: (a) supplying a computer modelling application with a set of structure coordinates of a molecule or molecular complex, at least a portion of the structural coordinates of the molecule or molecular complex being derived from, or defining the same relative spatial configuration as, at least a portion of the atomic coordinates corresponding to Ser30, Tyr 31, Asp 49, Trp90, and Ser91 of the light chain and Thr33, Tyr50, Asn52, Arg55, Tyr57, Lys74, Tyr99, AsplOl and Tyrl04 of the heavy chain of the OKT3 as set out in figure 5,

(c) evaluating the level of structural similarity between the agent and the molecule or molecular complex;

(d) structurally modifying the agent to increase the level of structural similarity of the agent with the molecule or molecular complex to yield a set of structure coordinates for a modified agent. In a preferred embodiment of the method steps (c) and (d) are conducted a plurality of times. In yet an even further aspect the invention provides a computer-assisted method for designing an agent capable of binding to CD3εγ including:

(a) supplying a computer modelling application with a set of structure coordinates of a molecule or molecular complex, at least a portion of the structural coordinates of the molecule or molecular complex being derived from, or defining the same relative spatial configuration as, at least a portion of the atomic coordinates corresponding to Ser30, Tyr 31, Asp 49, Trp90, and Ser91 of the light chain and Thr33, Tyr50, Asn52, Arg55, Tyr57, Lys74, Tyr99, AsplOl and Tyrl04 of the heavy chain of the OKT3 as set out in figure 5; (b) computationally building a model of an agent represented by a set of structure coordinates; and (c) determining the level of structural similarity of the model of the agent with the molecule or molecular complex, wherein a high level of structural similarity is indicative of potential binding to the CD3εγ. The invention also relates to ligands generated using these methods and their use in the treatment of condition mediation by binding to CD3εγ. As discussed previously this will include transplant rejection and autoimmune conditions. DESCRIPTION OF THE FIGURES Figure 1 Illustrates the amino acid sequence of the light chain of the OKT3 utilised in the present application.

Figure 2 Illustrates the amino acid sequence of the heavy chain of OKT3 utilised in the present application.

Figure 3 Illustrates the amino acid sequence for the CD3ε chain utilised in the present application. Figure 4 Hlustrates the amino acid sequence of the CD3γ chain utilised in the present application.

Figure 5 Hlustrates the structural coordinates of the CD3εγ in complex with the OKT3 ligand the present application.

Figure 6 Structure of the OKT3 Fab/CD3εγ complex Ribbon representation showing the heavy and light chain of OKT3 Fab fragment (coloured dark and light respectively) complexed to CD3εγ (ε = light, γ = dark).

Figure 7 Ribbon representation of the CD3εγ heterodimer, CD3ε = light, CD3γ = dark. Secondary structure assignments for the b-strands of the heterodimer are listed below. CD3ε chain are: residues 15-19 A; 22-27 B; 34-40 C; 42-44 C; 52-56 D; 5δ-63 E; 71-79 F

; δ9-95 G. For CD3γ chain are: residues 8-12 A; 18-25 B; 29-36 C; 38-45 C; 50-55 E; 59-

66 F ; 74-80 G.

Figure 8 Superposition of human and murine CD3ε subunits. Ca backbone shown only. Figure 9(a) and Figure 9(b) Interacting residues at the CD3εγ interface, in cpk format.

Positively charged residue (dark outline, grey inner, with white centre); negatively charged residues (dark outline, grey inner with grey centre); aromatic residues (grey outline, grey inner with light centre); polar residues (dark outline, grey inner, white centre); hydrophobic residues, (dark grey outline, grey inner, white centre). The residues are numbered. Figure 10 Interactions at the CD3εγ interface, displaying the network of H-bonds and the aromatic ladder.

Figure 11 Interactions at the CD3εγ interface, showing a buried intersubunit hydrophobic core. CD3ε = light, CD3γ = dark

Figure 12 Grasp representation of CD3εγ, with the OKT3 binding site mapped. Heavy chain and light chain of OKT3 are colour-coded dark and light respectively. The complementarity determining loops (CDR) of OKT3 are labelled. The significant electronegative strip on CD3ε (dark grey shading) is notable, and may indicate a binding site for a T-cell.

Figure 13 Grasp representation of CD3εγ, with the OKT3 binding site mapped. The electropositive strip of CD3ε (dark grey shading) is noted, and represents a potential binding site for another receptor.

Figure 14 Sequence alignment between the mouse and human CD3ε subunits, focussed on the area between the C and E strand. The human form has a unique 8 amino acid insert, which represent a duplication event. This area provides residues that contribute to the electronegative patch

Figure 15 The OKT3/CD3εγ interface. The interaction is mediated solely by CD3ε. A negative strip of CD3ε interacts with OKT3. The strip is made of 3 regions. 79-85, 34, 46-

48.

Figure 16 the negative strip of CD3ε (now in stick format) interacts with a negative strip of the OKT3 hypervariable site.

Figure 17 Detailed interactions at the CD3ε/ OKT3 interface, in ball-and-stick format, polar contacts represented as dashed lines. Figures 18(a) and(b) Surface plasmon resonance sensogram, measuring the affinity of the interaction between CD3εγ and OKT3. The interaction is 1.7 x 10-6 M, which is relatively weak for antibody/ antigen interactions, and is consistent with the small buried surface area of interaction between these components. As used in figure 5 the row labels are as follows:

1st column : ATOM statement

2nd column atom number

3rd column atom type

4th column residue type, or ligand type (such as water) 5th column = chain identifier

6th column = residue number

7th, 8th, 9th column = coordinates (x y z)

10th column = occupancy

11th column = temperature factor

A number of chain identifiers are also used.

Chain W= Water

Chain L= light chain of the OKT3

Chain H = heavy chain of the OKT3 Chain A= ε chain of CD3

Chain B = γ chain of CD3

Definitions A number of terms are used within the specification. Unless the contrary intention appears these definitions have the following meanings. The following amino acid abbreviations are used throughout this disclosure:

A= Ala= Alanine T = Thr = Threonine

V = Val = Valine C = Cys = Cysteine

L = Leu = Leucine Y = Tyr = Tyrosine I = He = Isoleucine N = Asn = Asparagine

P = Pro = Proline Q = Ghi = Glutamine

F = Phe = Phenylalanine D = Asp = Aspartic Acid

W = Trp = Tryptophan E = Glu = Glutamic Acid

M = Met = Methionine K = Lys = Lysine G = Gly = Glycine R = Arg = Arginine

S = Ser = Serine H = His = Histidine As used in this specification the term "structure coordinates" refers to Cartesian coordinates derived from mathematical equations related to the patterns obtained on diffraction of a monochromatic beam of x-rays by the atoms (scattering centres) of the crystal analysed. The diffraction data are used to calculate an electron density map of the repeating unit of the crystal. The electron density maps are then used to establish the positions of the individual atoms of the molecule making up the crystal. The term "binding domain," as used herein, refers to a region of a molecule or molecular complex, that, as a result of its shape, charge, hydrophobicity or hydrophilicity, is able to interact with another chemical entity. Thus, a binding domain may include or consist of features such as cavities, pockets, surfaces, or interfaces between domains. Chemical entities that may interact with a binding domain include, but -are not limited to, cofactors, substrates, inhibitors, agonists, and antagonists. As used herein the term "equivalent amino acid residues" means residues that are in the same position in the protein chain or have the same biophysical characteristics or have the same chemical characteristics. It will be understood by the skilled person that two amino acid residues may not be in the same absolute position of a protein sequence, yet still be equivalent. This is because all receptor proteins may not be of the same length. However, it is possible to "align" receptor protein sequences of different origin based on amino acid sequence similarities along the length of the protein. This process would be very simple for the T cell receptor proteins given the very high conservation of the gene sequence. A skilled person will also understand that certain amino acid residues have similar biophysical characteristics, and may therefore be substituted without having an appreciable effect on the biological activity of a protein. An example of a "conservative" amino acid substitution would be to substitute a non-polar residue such as valine, for the residue isoleucine, that is of a similar size and hydrophobicity. There are many such substitutions available, and it is unnecessary to detail every possible substitution herein. The skilled person would only need utilise routine experimentation to find an equivalent residue for an amino acid in a given protein. As used herein the term "identifying" encompasses either designing a new compound, selecting a compound from a group or library of previously known compounds or modifying a selected compound. The term "root mean square deviation" means the square root of the arithmetic mean of the squares of the deviations. It is a way to express the deviation or variation from a trend or object. The term "agent," as used herein, refers to chemical compounds, complexes of two or more chemical compounds, and fragments of such compounds or complexes. The term "agonist" refers to: a) a compound which has a conformation and polarity such that the compound itself binds to the binding domain of the selected receptor or a portion thereof; b) a compound which has a conformation and polarity such that the compound binds to the a molecule including the binding domain of a receptor or a fragment thereof at a site other than the binding domain, and this enhances or stabilises the binding of protein substrate and/or co-factor and/or interactor and/or ligand to the molecule; or c) a compound which has a conformation and polarity such that the compound binds to a receptor at a site other than the binding site, in which the binding has no effect on substrate, co-factor, or interactor/ligand binding but induces an effect the same as or similar to one which is induced by binding of substrate and/or co-factor and/or interactor to the receptor. It will be appreciated that a compound may have more than one of these abilities. As used herein the term structural similarity means having a similar conformational structure.

DETAILED DESCRIPTION OF THE INVENTION The present invention provides new methods, particularly computational methods, for the generation (through identification, design, or design de novo) of ligands of the CD3 receptor. Prior to the work described in the present application there was a lack of three dimensional structural information in relation to this receptor which was a severe impediment to rational drug discovery. Structure determination by X-ray crystallography. Described for the first time are crystals and three dimensional structural information in relation to the extracellular binding domain of the CD3 receptor bound to the known receptor ligand OKT3. OTK3 is a heterodimeric monoclonal antibody and the Fab fragment was used in the present invention. The sequences of the two chains used for the purposes of the present invention were as follows:

light chain

QΓVLTQSPAI MSASPGEKVT MTCSASSSVS YMNWYQQKSG TSPKRWΓYDT SKLASGVPAH FRGSGSGTSY SLTISGMEAE DAATYYCQQW SSNPFTFGSG TKLEINRADT APTVSIFPPS SEQLTSGGAS WCFLNNFYP KDESTVKWKID GSERQNGVLN SWTDQDSKDS TYSMSSTLTL TKDEYERHNS YTCEATHKTS TSPRVKSFNRNEC (SEQ ID: NO 1)

heavy chain

QVQLQQS GAELARPGAS VKMSCKASGY TFTRYTMHWV KQRPGQGLEW IGY1NPSRGY TNYNQKFKDK ATLTTDKSSS TAYMQLSSLTSEDSAVYYCA RYYDDHYCLD YWGQGTTLTV SSAKTTAPSV YPLAPVCGGT TGSSVTLGCLV KGYFPEPVT LTWNSGSLSS GVHTFPAVLQ SDLYTLSSSV TVTSSTWPSQ SITCNVAHPA SSTKVDKKIE PR (SEQ ID NO 2)

The native receptor was not used as the solubility of the native receptor is not sufficiently high to allow full characterisation. In addition the trans-membrane domain of the receptor is not involved in receptor activity per se and was thus not of direct interest. The studies described in this study therefore involved the purification and crystallisation of a mutant of the CD3 receptor. The mutant was one in which the a 26 amino-acid covalent linker was attached the C-terminus of CD3γ to link it to the N-terminus of CD3ε. It was envisaged that such an attachment would mimic the known receptor.

CD3ε

QTPYKVSI SGTTVELTCP QGPGSEILWQ HNDKNIGGDE DDKNIGSDED HLSLKEFSEL EQSGYYVCYP RGSKPEDANF YLYLRARV (SEQUENCE ID NO: 3)

CD3γ

MQ SIKGNHLVKV YDAQEDGSVL LTCDAEAKNI TWFKDGKMIG FLTEDKKKWN

LGSNAKDPRG MYQCKGSQNK SKPLQVYYRM (SEQUENCE ID NO: 4) Therefore, the human CD3εγ heterodimer was expressed and refolded using previously published protocol with the exception that a 26 amino-acid covalent linker was used to attach the C-terminus of CD3γ to the N-terminus of CD3ε. Two closely-migrating bands of the CD3εγ heterodimer were observed, only one of which interacted with OKT3. OKT3 was subsequently used as an immuno-affinity step and the corresponding Fab fragment as a vehicle for crystallisation and structure determination. The material was then crystallised using the hanging drop method. The initial characterisation of these type of crystals may be performed on any x-ray crystallography apparatus and is typically carried out on an in-house X-ray source at first instance. X-ray crystallography relies on the observation that if a parallel X-ray beam is passed through a molecule, the X-rays will be deflected by electron dense regions. The scattering of the parallel X-ray beam will give a diagnostic deflection pattern, depending on the structure of the molecule. It is observed that when molecules are in solution they are constantly changing conformation and are not aligned with their neighbouring molecules, meaning that the X-ray diffraction will be diffuse and non-interpretable. Fortunately if all of the molecules of a similar type are aligned in an orderly fashion for example, as they are in a crystal, then X-ray diffraction will be orderly and the pattern of diffraction contains structural information about the molecule within the crystal. In X-ray crystallography, a crystal of, for example, protein is bombarded with X-rays whilst it is rotated through an angle of 90°, thus allowing a 'data set' to be collected. Data is collected on an image plate or photographic film and interpreted by computer software due to the enormous number of data points and intensities collected. The three dimensional structure of the heterodimeric receptor/ligand complex can be determined in this manner. This process was followed for the CD3/OKT3 complex and the present invention provides a crystal of an CD3 receptor/OKT3 complex for the first time. The crystals obtained by the methodology were large with the dimensions (a,b,c) of the unit cell being such that a is from about 45 angstroms to about 85 angstroms, b is about 45 angstroms to about 65 angstroms and c is about 80 angstroms to about 120 angstroms. In the preferred embodiment of the crystals of the present invention the structural dimensions were a= 67.7, b = 55.5, c = 96.05 angstroms, hi this preferred embodiment, the crystal preferably has angles α=90°, β=100.85°, γ=90°. The crystal structure of OKT3-Fab/ CD3εγ heterodimer was determined by using a combination of molecular replacement and iterative model building and refinement. The final 2.1 A model, comprising all residues of the OKT3-Fab, residues 11-96 of CD3ε and 1-81 of CD3γ has an R_factor and R_free of 21.1% and 25.5% respectively. The quality of the electron density is excellent and moreover is unambiguous for the residues at the CD3ε/CD3γ interface and at the antibody/ antigen interface. The structure of the crystal provides useful information as to the binding domain of the CD3 itself as well as the binding domain of the ligand OKT3. It therefore provides two possible approaches to the generation of ligands to the receptor. hi analysing the x-ray crystallographic data it is noted that each of the amino acids contained within the structure is defined by a set of structure coordinates as set forth in Figure 5. Slight variations in structure coordinates can be generated by mathematically manipulating the structure coordinates obtained. For example, the structure coordinates given in Figure 5 could be manipulated by crystallographic permutations of the structure coordinates, fractionalisation of the structure coordinates, integer additions or subtractions to sets of the structure coordinates, inversion of the structure coordinates or any combination of the above. Alternatively, modifications in the crystal structure due to mutations, additions, substitutions, and/or deletions of amino acids, or other changes in any of the components that make up the crystal, could also yield variations in structure coordinates. Such slight variations in the individual coordinates will have little effect on overall shape of the receptor. If such variations are within an acceptable standard error as compared to the original coordinates, the resulting three-dimensional shape is considered to be structurally equivalent. It would be clear to a skilled addressee that slight variations in individual structural coordinates of the crystal would not significantly effect the overall shape and configuration of the binding domain described. Such slight variations would therefore not be expected to significantly alter the nature of chemical entities such as ligands that could associate with the substrate binding domain. As such slight variations of this type are not expected to significantly effect the potential class of agonists or antagonists identified. In a preferred embodiment of the invention the crystal of the CD3/OKT3 complex has at least 3 atoms with atomic coordinates defining the same relative (within 2.1 angstrom) spatial relationship as 3 atoms in the structure represented by the structural coordinates listed in figure 5. hi a particularly preferred embodiment a crystal is provided having a plurality of atoms with atomic coordinates defining the same relative (within 1.5 angstrom) spatial relationship as a corresponding plurality of atoms in the structure represented by the structural coordinates listed in figure 5. In a most preferred embodiment the crystal comprises atoms arranged in the same spatial relationship represented by the structural coordinates listed in figure 5. Important information on the structure of the binding domain of both the CD3 receptor and the CD3 recognition binding domain of the OKT3 ligand can be gleaned from the crystal structure data provided by the present invention.

The human CD3εγ structure The CD3εγ heterodimer measures approximately 57 A by 38 A by 31 A, with the strands at the top of the subunits fanning outwards to form a concave γ/ε depression measuring approximately 5θA across and 25A wide. The heterodimer is orientated such that the C-terminal tails, which connect the stalk regions to the membrane, are at the bottom of the figure. The CD3ε monomer, measuring approximately 35A by 31 A by 29 A, contains eight β-strands that form two anti-parallel β-sheets (sheet A: strands A, B, E, D; sheet B: strands C, C, F, G). The sheets pack against each other via a hydrophobic interior that includes two cysteine residues (Cys 27, Cys 76) located at the top of the B β-strand and in the middle of the F-strand respectively, that form a canonical disulfide bond, which packs against the hydrophobic-core residues Trp 37, and Tyr 14. Accordingly, the human CD3ε monomer adopts the I-set immunoglobulin (Ig) fold. The β-strands of sheet A are approximately uniform in length (5-6 residues in length) whereas the β-strands on the β- sheet B are more variable in length and curvature (3-9 residues long). For example, the C and F-strands are observed to lean towards the front β-sheet, presumably as a consequence of the disulfide, to make a number of contacts with the B-C loop. This loop, together with the C'-D loop, represent the most mobile regions of the CD3ε molecule; the surface- exposed C'-D loop, which makes no contacts with the core of the molecule, contains four acidic residues, Asp 47, Glu 48, Asp 49, Asp 50, within a type I β-turn. The CD3γ subunit, comprising 82 residues, measuring approximately 42 A by 30 A by 32A, contains 7 β strands that form two anti-parallel β-sheets (sheet A, strands A, B, E; sheet B: strands C, C, F, G), with a disulfide (Cys 24 to Cys 65) that connects the top of the B-β strand to the F-strand, that packs against the core residue, Trp 33. Accordingly the CD3γ protomer adopts the C2-set Ig fold. Strand A appears to terminate prematurely, with residues 12-15 of the A-B loop bulging away from the B-strand, enabling this region to participate in intersubunit interactions. Indeed the A β-strand is the shortest secondary structural element of CD3γ, whereas a number of the β-strands of CD3γ are 8 residues long. Although the sequence identity between CD3ε and CD3γ is only 20%, the subunits share significant structural homology, with 49 Cα atoms having an r.m.s.d of 1.53 . The structurally-conserved regions include the B, C, C E, F and G strands, the B-C loop and the C-C loop. CD3γ notably does not contain the equivalent of the D strand of CD3ε, thereby explaining the different Ig-topology of the subunits. The conserved core packing residues are Val 16 (A strand), Val 23, Leu 25 Cys 27 (B strand), He 35, Tip 37 (C strand), He 44 (C strand), Leu 62 (E strand), Tyr 74, Cys 76 (F strand), Leu 90 and Leu 92 (G strand). The large structural differences between the CD3ε and CD3γ subunits reside at the extreme N-terminus, the A strand, the A-B loop, residues 30-33, residues 45-58, residues 64-70, and residues 78-88. Although CD3ε and CD3γ both have an A-strand, their orientation with respect to their respective B sheets is quite different. In CD3ε, the A and G strands are almost parallel, whereas in CD3γ, the end of the A strand and the start of the a-b loop is orientated away from the G strand. As a consequence, the CD3γ A- strand is less exposed to solvent in comparison to its CD3ε counterpart. The CD3εγ heterodimer comprises 3 layers or β-sheet, with a large and central, mixed, 8-stranded β sheet that is flanked on either side by a 4- and 3-stranded antiparallel β -sheets from CD3ε and CD3γ respectively. The two protomers interact side-on, with an approximate 2-fold (173° rotation) relationship between the two subunits, such that the A β-sheets of these subunits face the opposite sides of the molecule. The CD3εγ interface is extensive, with a buried surface area of 1845 A² upon complexation, and also exhibits high shape complementarity (0.76). The interface involves the A-strand, the C-C loop, the F and G strands from CD3ε; the interacting elements from CD3γ are the extreme N-terminus (residues 1-7), one residue within the A-strand (Val 11), one residue within the F-strand (Met 62) and extensive interactions arising from the G-strand . The extreme N-terminus of CD3γ folds back sharply towards , and interacts extensively with CD3ε. Overall at the interface, there are 16 hydrogen bonds, 3 salt bridges and a significant area of hydrophobic interactions. The CD3εγ interface largely excludes water molecules, and only 2 water- mediated hydrogen bonds are observed, one of which is at the periphery, whilst the other is buried in the middle of the interface. The salt bridges (Glu 84ε to Lys73γ; Asp 85ε to Lys73γ) are at the "bottom" of the interface, whereas the other salt bridge (Arg93ε to Aspl3γ) is located at the upper end of the interface. Of the direct hydrogen bonds, 7 are main chain /main chain interactions between the G strands of the respective subunits, resulting in the continuation of the B β-sheets to form the large central sheet structure. The hydrophobic core of one side of the interface is dominated by an aromatic ladder (His 7γ, Tyr 89ε, Tyr 73ε, Tyr 91ε, Tyr 79γ) that traverses the entire length of the molecule, with some of these aromatic residues also forming vdw interactions with the aliphatic moieties of the long side chains of Lysl Oγ, and Arg 93ε. The polar groups of His 7γ, Tyr 91ε, Tyr 73ε, also mediate intersubunit hydrogen bonds. The other hydrophobic-interacting interface involves the A strand of CD3ε. The topology of the CD3ε domain is such that the inward facing hydrophobic residues of the A strand does not interact with the corresponding CD3ε G-strand residues, and consequently does not form part of the hydrophobic core of the CD3ε subunit. Instead, it can be viewed that the neighbouring CD3γ G-strand acts as a surrogate partner, stabilising the otherwise exposed hydrophobic interior, where the long side chains of the CD3γ subunit interact with the hydrophobic core residues of the A strand of CD3ε. Analysis of the structure indicates that the surface residues of the heterodimer are

Thr 12, Pro 13, Lys 15, Ser 17, Ser 19, Gly 20, Thr 21, Thr 22, He 24, Thr 26, Gln 29, Pro 31, Ser 33, Glu 34, Asn 40, Asp 41, Lys 42, Asn 43, Asp 47, Glu 48, Asp 49, Asp 50, Lys 51, Asn 52, Asp 56, Glu 57, Asp 58, His 59, Ser 61, Lys 63, Glu 64, Ser 66, Glu 67, Leu 68, Glu 69, Arg 79, Lys 82, Pro 83, Glu 84, Asp 85, Asn 87, Arg 95 of the epsilon chain and Gln 1, Ser 2, Lys 4, Asn 6, Tyr 12, Asp 13, Ala 14, Glu 16, Asp 17, Thr 23, Asp 25, Glu 27, Ala 28, Lys 29, Asp 36, Lys 38, Thr 44, Glu 45, Asp 46, Lys 47, Lys 48, Lys 49, Asn 51, Ser 54, Ala 56, Lys 57, Asp 58, Arg 60, Lys 66, Ser 68, Gln 69, Asn 70, Lys 71, Lys 73, Arg 80 of the gamma chain of CD3. Analysis of the surface residues indicates that there is an acidic region defined by Glu 48, Asp 49, Asp 56, Glu 57, Asp 58, Glu 64, Glu 69 on the epsilon surface. In addition analysis indicates that there is an electropositive patch defined at Lys 35, Lys 38, Lys 57, Arg 60, Lys 66, Lys 71, Lys 73 of the gamma chain.

Comparison to the murine CD3εγ structure The human CD3ε and CD3γ sequences shares 41% and 43% sequence identity to its murine counteφarts respectively, with the human CD3εγ crystal structure resembling the previously determined NMR structure of murine CD3εγ heterodimer; the r.m.s deviations for the pairwise superpositions of the individual CD3 subunits are 1.27A (for 58 Cα residues) and 1.50A (for 46 Cα residues) for CD3ε and CD3γ respectively, which is reflective of conserved core-packing residues between the structures. Nevertheless, within this conserved framework, the assignment of secondary structure appeared to be more well-defined in the human CD3εγ structure, which may reflect differences in the techniques employed in deteimining the human and murine CD3εγ structures. In addition, the main chain intersubunit hydrogen bonding of the G-strands was observed to be more extensive in the human structure (eight main-chain hydrogen bonds), compared to the murine form where only three G/G-strand mediated hydrogen bond was observed in the NMR ensemble. In addition, there are significant differences between the human and murine CD3εγ structures. Of the 86 residues of the human CD3ε monomer, and the 81 residues of the human CD3γ monomer , 33% and 46% of the residues are structurally dissimilar to the murine counterparts respectively. The largest differences between CD3ε structures are within the B-C loop (residues 30-34), the region containing the additional D strand (residues 41-56) and the F-G loop (79-87); whilst the most significant differences between CD3γ structures reside within the extreme N-terminus (residues 1-17, a region which includes the A-strand), the B-C loop (residues 26-31) residues 42-48 (part of C" strand and following loop) and a region within the F-G loop (residues 67-71). Moreover, when comparing the CD3εγ heterodimer, only 76 Cα residues superpose with an r.m.s.d of 1.4A. The poor superposition of the intact heterodimer reflects a significant difference in the quaternary arrangement of the respective subunits, whereupon superposition of the human and murine CD3ε subunits, a 23° rotation is required to superpose the corresponding CD3γ subunits. This differential juxtapositioning of the ε and γ subunits arise from differing features of the respective interfaces. The BSA for the murine CD3εγ interface is 1090A², whereas the BSA of the human CD3εγ interface, at 1845 A², is significantly larger. This surprising difference arises largely, but not exclusively, from the diversity within the N- terminal regions of the human and murine CD3γ chains, where in the human structure is intimately involved in dimer contacts, whereas in the murine form the equivalent region extends into solution. Nevertheless, some similarities between the human and murine structures, principally involving conserved aromatic residues, are observed at the interface. For example, the aromatic ladder observed in the human structure is largely conserved in the murine structure (apart from His 7γ), and some of the additional intersubunit interactions these residues participate in are also conserved. The double Tyr pairing from the F strand in CD3γ participates in conserved interactions between the species. In addition the aromatic residues at the other face of the interface, namely Tyr 14ε and Tyr 78γ and are conserved, and make analogous interactions at the interface between the species. Another interesting divergence between the murine and human CD3εγ structures is their respective electrostatic properties. The human CD3εγ heterodimer contains two patches of electronegative charge, in close proximity to one another, localised solely on one face of the CD3ε subunit. The majority of residues that contribute to this electronegative cluster arise from the unique insertion between the C-E strands (residues E48, D49, D56, E57, D58) of human CD3ε. Accordingly, the corresponding feature is absent in the murine structure, although an acidic patch (residues El 8, D24, D26, D43, D50), on the same face of CD3ε was observed. Notably, there is also a long and narrow band of electropositive charge that runs diagonally along the GFCC sheet of human CD3γ (residues K35, K38, K57, R60, K66, K71, K73, R80); a basic cluster, of lesser magnitude, but nevertheless on the same face of the human CD3γ basic cluster, was observed in the murine CD3γ structure.

The OKT3/CD3εγ interface The CD3εγ heterodimer is perched centrally within the OKT3 hypervariable site at an angle of approximately 45° with respect to the two-fold axis of the OKT3 Fab fragment.

It can be clearly seen that CD3ε solely mediates contacts with OKT3, and that CD3γ is distant from the interface. The buried surface area at the interface is merelyl 140 A², a value that does not fall within the previously observed range of other antibody/ antigen interactions (3HFL, 1700 A², 3HFM = 1625 A²; IVFB, 1720A²; 2JEL, 1700 A²; 1VCA, 1970 A²; N15/H57 interface : 1600A²). Only a small fraction of OKT3's hypervariable site mediates binding, nevertheless the interface exhibits high shape complementarity

(0.75), a value that is more typical for antibody/ antigen interactions. CD3ε contributes approx. 630A² to the interface, while OKT3 contributes approx. 5lθA², 69% of which arises from the heavy chain, and 31% from the light chain. The CDR2 and CDR3 loops are the principal contributors from the heavy chain (BSA 200A², and 105 A² respectively), with CDR1 and HV4 contributing less BSA upon complexation (26 A² and 20 A² respectively). CDR3 and CDR1 are the principal contributors from the light chain (84 A² and 60 A² respectively), whereas CDR2 is minimally involved (15 A²). Overall, there are 4 salt bridges, 8 hydrogen bonds, 5 water-mediated hydrogen bonds, and a number of van der Waals interactions that are almost exclusively via aromatic residues arising from the OKT3 hypervariable site. Of the water-mediated hydrogen bonds, four arise from the light chain, The three salt bridges are Asp 49(L) to Lys 82ε, Lys74(H) to Glu 48ε, Arg 55 (H) to Glu48ε, Asp 101(H) to R79ε. The narrow strip of OKT3 residues interact with a narrow strip of CD3ε (approximately 3θA long and 5 A wide), which comprises 3 discontinuous regions, residues 79-85 (the F-G loop), residue 34 (1^st residue of the C- strand), and stretch 46-48 ( the C-D loop). The Glu 34 sidechain projects into the hypervariable site, forming hydrogen bonds with two residues from CDRH2 (Tyr 50 and Asn 52), as well as the aliphatic moiety of Glu 34 packing against Tyr 57 (CDR2), the side chain of which also forms a water-mediated h-bond to the main chain of Glu 34 main chain Glu 34 immediately abuts to the F-G loop, forming a salt bridge with Arg 79 from this loop. The large F-G loop (residues 80-88), which contains a mini-helical region, is well-ordered, despite it forming limiting contacts with the core of the CD3ε monomer; Pro 83 was observed to pack against the aromatic ring of Tyr 77, and Phe 88, at the base of this F-G loop, sits in a pocket formed within the loop prior to the A-strand, packing against the aliphatic side chain of Gln 11 and Tyr 14, as well as making inter-subunit contacts. The F-G loop is very polar , containing two basic residues (Arg 79, Lys 82), Glu 84 (does not form any interactions with OKT3) and Asp 85 which forms a H-bond with Ser 30 (Ll). Gly 90, Ser 91, for h-bonds with the main chain of L3, the N-terminal region of this loop is nestled in a bed of aromatics (Trp 90(L3), Tyr 31 (Ll), Tyr 99, Tyr 104 (both from H3). There is a water-filled cavity between residue 34 and the next interacting region (46- 48). This region originates from the unique insert in human CD3ε. This interaction involves two long basic sidechains, - Arg 55 (H) and Lys 74(h) forming a salt bridge with Glu 48, and Arg 55 forming a direct H-bond to Gly46 (main chain). A summary of the variable domain contacts is given below.

TABLE 1 Variable domain contacts of OKT3 with the CD3 heterodimer. Light chain CD3ε Interaction Ser 30 °^r Asp85 ^oδ2 H-bond Ser 30 * Lys82^N, Asρ85 ^oδ2 Water-mediated H-bond Tyr31 ^0η Gly80 ° H-bond Tyr31 ^{c Cε2} Gly80, Lys82 vdw Asp49 ^oδ2 Lys82 ^Nζ Salt bridge Asp49 ^oδ2 Lys82 ^Nζ Water-mediated H-bond Trp90 ° Gly80 ° H-bond Tφ90 ° Arg79 ° Water-mediated H-bond Tφ90 ^cδ2' ^Cε2' ^Cε3' ^cζ2 Gly80, Arg79_: , Ser81 vdw Ser91 ° Serδl °* H-bond Ser91 ° Ser81 ^0γ Water-mediated H-bond

Heaw chain CD3ε Interaction Thr33 ^Cγ2 Arg79 vdw Tyr50^0η Glu34^0εl H-bond Tyr50 ^0η Glu34 ^N Water-mediated H-bond Asn52 ^Nδ2 Glu34 ^0ε2 H-bond Arg55 ^Nηl Gly46 ° H-bond Arg55^Nηl Glu 48^0ε2 Salt bridge Arg55 ^Cγ'^Cδ Glu 4δ vdw Tyr57 ^0η Glu34 ^N H-bond Tyr57 ^cδ2'^{Cε2, cζ} Glu34 Vdw Lys74 ^Nζ Glu4δ ^0εl Salt bridge Tyr99 ^0η GlyδO Vdw AsplOl ^oδl'^oδ2 Arg79 ^Nη2'^Nε Salt bridge Tyrl04^{Cεl, Cε2, Cζ} Lys82, Ser81, GlyδO, Pro δ3 Vdw

With reference to the above table it can be seen that the crucial residues for binding are amino acids Glu34, Gly46, Glu4δ, Arg79, GlyδO, Serδl, Lysδ2, Pro83, Asp 85 of CD3ε. It is also clear that the crucial residues for binding of the OKT3 are Ser30, Tyr 31, Asp 49, Tφ90, and Ser91 of the light chain and Thr33, Tyr50, Asn52, Arg55, Tyr57, Lys74, Tyr99, AsplOl and Tyr 104 of the heavy chain of the OKT3. Table 2 contacts between the two chains of the heterodimer.

CD3ε CD3γ Interaction

Prol3^Cα'^cβ,c Gln76 Vdw Tyrl4^N Gln76^0εl H-bond Tyrl4° Gln76 ^Nε2 H-bond Tyrl4^Cβ,Cγ,Cδl Gln76 Vdw y_all6Cβ,Cγl,Cγ2 Tyr78 Vdw

Ilel8CB,^Cγl'^Cγ2 Arg 80 Vdw Asp 41 ^Cγ Glnl Vdw Asp41^0δ2 _{Gln l}N,Nε2 H-bond Asp41^0δl Ser2^N Water-mediated H-bond Tyr 73 Lys 10 vdw Tyr73 °^η Val 11 ^N H-bond Glu δ4 ° Lys 73 ^Nζ H-bond Asp85^0δl Lys73 ^Nζ Salt bridge Glu84^cβ'^Cδ Lys 4 vdw

Glu 4 θε2 Lys4^Nζ Salt bridge Ala δ6 His7^Nε2 H-bond Lys73 ^Nζ H-bond

Phe 88 ^Cδ2' ^Cεl' ^Cε2' ^Cζ Pro 74 , Met 62, Gln 76 vdw

Tyr 89 ^υ Gln 76 ^N H-bond

Tyr 89 N Pro74 o Water-mediated H-bond

Tyr 89 ^Cγ' ^Cδl' ^Cεl' ^{cδ2, Cε2, Cζ} His 7 vdw

Leu 90 ⁵¹ Tyr 78 vdw

Tyr 91 ^N Gln76° H-bond

Tyr 91^0η Asp 13 ^oδl H-bond

Tyr 91° Tyr 78 ^N H-bond

Tyr 91 ^cr>^cδl> ^εl>^CS2>^cζ Val 11, Tyr 79 vdw

Leu 92 ^Cδl Tyr78 vdw

Arg 93 ^N Tyr7δ° H-bond

Arg 93° Arg 0^N H-bond

Arg93^Cβ'^Cγ Tyr 79, Met 81 vdw Arg93 ^Nηl Asp 13 ^0δ2 Salt bridge Arg 95 ^N Arg 80 ° H-bond Arg 95 ° Arg δO ^Nηl H-bond

The significance of the provision by the applicant of the crystal structure referred to above is mainly that the provision of this data allows, for the first time unambiguous insight into the binding domain of the receptor as well as the portion of the monoclonal antibody OKT3 that recognises and binds to the receptor. As will be discussed later in this specification the knowledge provided by the binding domain and the absolute configuration of the domain of either the provides valuable information that the skilled drug developer can use in developing molecules that can bind to the domain. In an alternative the receptor recognising domain and the configuration thereof of the ligand provided by the crystal structure allows for the design of molecules that may mimic the behaviour of the ligand. The compounds generated through the use of the data can therefore be used to block processes that require binding to the domain to occur. As stated previously this receptor is associated with T-cell receptor signalling. As such these compounds would be expected to by useful therapeutics in the treatment of conditions such as transplant rejection and autoimmune diseases. Examples of autoimmune diseases that may be amenable to treatment with molecules of this type include Multiple sclerosis, Myasthenia gravis, Guillain-Barre, Autoimmune uveitis, Crohn's Disease, Ulcerative colitis, Primary Bilary cirrhosis, Autoimmune hepatitis Autoimmune hemolytic anemia, Pernicious anemia, Autoimmune thrombocytopenia, immune mediated diabetes mellitus, Grave's Disease, Hashimoto's thyroiditis, Autoimmune oophoritis and orchitis, Autoimmune disease of the adrenal gland, Temporal arteritis, Anti-phospholipid syndrome, Vasculitides such as Wegener's granulomatosis, Behcet's disease, Rheumatoid arthritis, Systemic lupus erythematosus, Psoriasis, Scleroderma, Dermatitis heφetiformis, Polymyositis, dermatomyositis, Pemphigus vulgaris, Spondyloarthropathies such as ankylosing spondylitis, Sjogren's syndrome and Vitiligo.

CD3 BINDING DOMAIN The provision of the crystal structure information has allowed the applicants to determine the binding domain of the CD3εγ heterodimer. The present invention therefore provides a binding domain or portion thereof of the CD3 receptor. The receptor is a hetero-dimeric receptor and amino acid sequences for the portions of the epsilon and gamma chains utilised in the present study are provided in figures 3 and 4. The data provided by the present invention in identifying the binding domain provides important information that will enable the activity of this receptor to be probed. As will be apparent to a skilled addressee binding domains (sometimes called binding pockets) are of significant interest and utility in fields such as drug discovery. The association of natural ligands or substrates with the binding pockets of their corresponding receptors or enzymes is the basis of many biological mechanisms of action. Similarly, many drugs exert their biological effects through interaction with the binding pockets of receptors and enzymes. Such interactions may involve either part or the entire binding domain. An understanding of the structural interactions between the ligand and the binding domain helps lead to the design of drugs having more favourable interactions with the target that in turn lead to improved biological effects being observed. Therefore, information in relation to the structure of the binding domain is valuable in designing potential ligands for the receptor. As discussed above such ligands could potentially act as inhibitors of the receptor that should be useful in therapies aimed at reducing transplant rejection and or the treatment of autoimmune diseases. The information can also be used to provide molecules or molecular complexes including this domain. These molecules and molecular complexes would be expected to have similar activity as the native receptor. This mimicking of the natural activity may be useful in certain applications. The applicants have thus crystallised and defined the limits of a stable domain of CD3εγ receptor. The domain incoφorates the binding region of CD3εγ and therefore provides significant information in respect of the crucial moieties for ligand binding to the domain. The present invention therefore provides a binding domain or portion thereof of

CD3, especially CD3εγ. i a preferred embodiment the domain is the extracellular binding domain, hi one preferred embodiment the binding domain includes at least one amino acid selected from the group consisting of: Thr 12, Pro 13, Lys 15, Ser 17, Ser 19, Gly 20, Thr 21, Thr 22, He 24, Thr 26, Gln 29, Pro 31, Ser 33, Glu 34, Asn 40, Asp 41, Lys 42, Asn 43, Asp 47, Glu 48, Asp 49, Asp 50, Lys 51, Asn 52, Asp 56, Glu 57, Asp 58, His 59, Ser 61, Lys 63, Glu 64, Ser 66, Glu 67, Leu 68, Glu 69, Arg 79, Lys 82, Pro δ3, Glu δ4, Asp δ5, Asn 87, Arg 95 of the epsilon chain of CD3εγ or an equivalent amino acid residue. A particularly preferred domain within this domain includes at least one amino acid selected from the group consisting of Glu 48, Asp 49, Asp 56, Glu 57, Asp 58, Glu 64, Glu 69 or an equivalent amino acid residue. Another preferred domain on the epsilon chain includes one or more amino acid residues selected from the group consisting of residues Glu34, Gly46, Glu48, Arg79, GlyδO, Serδl, Lysδ2, Pro83, Asp 85 or an equivalent amino acid residue. In a further preferred embodiment the binding domain includes at least one amino acid selected from the group consisting of: Gln 1, Ser 2, Lys 4, Asn 6, Tyr 12, Asp 13, Ala 14, Glu 16, Asp 17, Thr 23, Asp 25, Glu 27, Ala 28, Lys 29, Asp 36, Lys 38, Thr 44, Glu 45, Asp 46, Lys 47, Lys 48, Lys 49, Asn 51, Ser 54, Ala 56, Lys 57, Asp 58, Arg 60, Lys 66, Ser 68, Gln 69, Asn 70, Lys 71, Lys 73, Arg δ0 of the gamma chain of CD3εγ or an equivalent amino acid residue. A particularly preferred domain within this binding domain includes at least one amino acid selected from the group consisting of Lys 35, Lys 38, Lys 57, Arg 60, Lys 66, Lys 71, Lys 73 or an equivalent amino acid residue. It is particularly preferred that the domains includes at least two amino acid residues from the stated groups, even more preferably at least three amino acid residues, yet even more preferably at least four, more preferably at least 5 amino acids from the stated groups, most preferably all amino acids. In a particularly preferred embodiment the amino acid residues of the binding domain are located in the same relative spatial relationship as the corresponding amino acid residues in figure 5. As will be appreciated it would be possible using the information provided by the applicants in identifying the binding domain to design molecules and molecular complexes that mimic the CD3εγ heterodimer. These molecules or molecular complexes could be utilised in probing the properties of the receptor as efficiently as the receptor protein itself. The present invention therefore provides a molecule or molecular complex wherein at least a portion of the structural coordinates of the molecule or molecular complex define the same relative spatial configuration as at least a portion of the structure coordinates of the CD3εγ receptor as set out in figure 5. In one preferred embodiment at least a portion of the coordinates of the molecule or molecular complex define the same relative spatial configuration as at least a portion of the coordinates of the binding domain defined by amino acid residues Thr 12, Pro 13, Lys 15, Ser 17, Ser 19, Gly 20, Thr 21, Thr 22, He 24, Thr 26, Gln 29, Pro 31, Ser 33, Glu 34, Asn 40, Asp 41, Lys 42, Asn 43, Asp 47, Glu 48, Asp 49, Asp 50, Lys 51, Asn 52, Asp 56, Glu 57, Asp 5δ, His 59, Ser 61, Lys 63, Glu 64, Ser 66, Glu 67, Leu 68, Glu 69, Arg 79, Lys δ2, Pro 83, Glu 84, Asp 85, Asn 87, Arg 95 of the epsilon chain of CD3εγ or an equivalent amino acid residue. A particularly preferred molecule or molecular complex is one in which at least a portion of the coordinates of the molecule or molecular complex define the same relative spatial configuration as at least a portion of the coordinates of a binding domain defined by amino acid residues Glu 48, Asp 49, Asp 56, Glu 57, Asp 58, Glu 64, Glu 69 of the epsilon chain of CD3εγ. In a most preferred embodiment the molecule or molecular complex has coordinates that define the same relative spatial configuration as at least two amino acid residues from the stated group, even more preferably at least three amino acid residues, yet even more preferably at least four, more preferably at least 5 amino acids from the selected group, most preferably all amino acids. In another preferred embodiment at least a portion of the coordinates of the molecule or molecular complex define the same relative spatial configuration as at least a portion of the coordinates of the binding domain defined by amino acid residues Gln 1, Ser 2, Lys 4, Asn 6, Tyr 12, Asp 13, Ala 14, Glu 16, Asp 17, Thr 23, Asp 25, Glu 27, Ala 28, Lys 29, Asp 36, Lys 38, Thr 44, Glu 45, Asp 46, Lys 47, Lys 48, Lys 49, Asn 51, Ser 54, Ala 56, Lys 57, Asn 58, Arg 60, Lys 66, Ser 68, Gln 69, Asn 70, Lys 71, Lys 73, Arg 80 of the gamma chain of CD3εγ or an equivalent amino acid residue. A particularly preferred molecule or molecular complex is one in which at least a portion of the coordinates of the compound or molecular complex define the same relative spatial configuration as at least a portion of the coordinates of a binding domain defined by amino acid residues Lys 35, Lys 38, Lys 57, Arg 60, Lys 66, Lys 71, Lys 73 of the gamma chain of CD3εγ or an equivalent amino acid residue, hi a most preferred embodiment the molecule or molecular complex has coordinates that define the same relative spatial configuration as at least two amino acid residues from the stated group, even more preferably at least three amino acid residues, yet even more preferably at least four, more preferably at least 5 amino acids from the stated group, most preferably all amino acids. In another preferred embodiment at least a portion of the structural coordinates of the molecule or molecular complex define the same relative spatial configuration as at least a portion of the coordinates of residues Glu 34, Gly 46, Glu 48, Arg 79, Gly 80, Ser 81, Lys 82, Pro δ3, Asp δ5 of the epsilon chain of CD3εγ as shown in figure 5. It is particularly preferred that at least a portion of the coordinates of the molecule or molecular complex define the same relative spatial configuration as a plurality of these amino acid residues. In a most preferred embodiment at least a portion of the structure coordinates of the molecule or molecular complex define the same relative spatial configuration as the coordinates of Glu34, Gly46, Glu4δ, Arg79, GlyδO, Serδl, Lysδ2, Pro83, Asp 85 in figure 5. In another preferred embodiment at least a portion of the structural coordinates of the molecule or molecular complex define the same relative spatial configuration as at least a portion of the structure coordinates of the atoms of the CD3ε chain identified in table 1 as being involved in binding of the CD3εγ to OKT3. It is preferred that the molecule or molecular complex is capable of binding to the monoclonal antibody OKT3. Binding Domain of the Ligand. The provision of the crystal structure information has also allowed the applicants to determine the CD3 recognising binding domain of the ligand OKT3. The present invention therefore provides a binding domain or portion thereof of the ligand OKT3. The ligand is a hetero-dimeric ligand and amino acid sequences for the portions of the light and heavy chains utilised in the present study are provided in figures 1 and 2. The data provided by the present invention in identifying the CD3 recognising binding domain of OKT3 allows the activity of this monoclonal antibody to be probed. The knowledge of the binding domain of the ligand that I involved in the interaction with the CD3εγ allows for the generation of molecules or molecular complexes that would be expected to have similar behaviour. In effect this thus allows for the rational drug design of potential ligands for the Domain that would be expected to have similar activity to the monoclonal antibody itself. The applicants have thus crystallised and defined the limits of the CD3εγ recognising domain of the monoclonal antibody OKT3. The domain incoφorates the binding region of OKT3and therefore provides significant information in respect of the crucial moieties for ligand binding to the CD3εγ. The present invention therefore provides a binding domain or portion thereof of the OKT3 ligand. A preferred domain includes one or more amino acid residues selected from the group consisting of residues Ser30, Tyr 31, Asp 49, Tφ90, and Ser91 of the light chain and Thr33, Tyr50, Asn52, Arg55, Tyr57, Lys74, Tyr99, AsplOl and Tyrl04 of the heavy chain of the OKT3 or an equivalent amino acid residue. It is particularly preferred that the domain includes at least two amino acid residues from this group, even more preferably at least three amino acid residues, yet even more preferably at least four, more preferably at least 5 amino acids from the selected group, most preferably all amino acids. In a particularly preferred embodiment the amino acid residues of the binding domain are located in the same relative spatial relationship as the corresponding amino acid residues in figure 5. As will be appreciated it would be possible using the information provided by the applicants in identifying the binding domain to design molecules and molecular complexes that include this binding domain. These molecules or molecular complexes could be utilised in probing the properties of the receptor as efficiently as the receptor protein itself. The invention therefore also relates to molecules or molecular complexes including the binding domain of the invention, yet a further aspect the invention provides a molecule or molecular complex including at least a portion of a OKT3 binding domain, wherein the binding domain includes at least one amino acid residue selected from the group consisting Ser30, Tyr 31, Asp 49, Tφ90, and Ser91 of the light chain and Thr33, Tyr50, Asn52, Arg55, Tyr57, Lys74, Tyr99, AsplOl and Tyrl04 of the heavy chain of the OKT3 or an equivalent amino acid residue. It is preferred that the molecule or molecular complex is capable of binding to the CD3εγ heterodimer. In a particularly preferred embodiment the invention provides a molecule or molecular complex including a binding domain or portion thereof wherein the binding domain includes a plurality of amino acid residues selected from the group consisting Ser30, Tyr 31, Asp 49, Tφ90, and Ser91 of the light chain and Thr33, Tyr50, Asn52, Arg55, Tyr57, Lys74, Tyr99, AsplOl and Tyrl04 of the heavy chain of the OKT3 or an equivalent amino acid residue. The domain of the molecule includes at least two amino acid residues from this group, even more preferably at least three amino acid residues, yet even more preferably at least four, more preferably at least 5 amino acids from the selected group, most preferably all amino acids. In a particularly preferred embodiment the amino acid residues of the binding domain of the molecule or molecular complex are located in the same relative spatial relationship as the corresponding amino acid residues in figure 5. The invention also provides a molecule or molecular complex wherein at least a portion of the structural coordinates of the molecule or molecular complex define the same relative spatial configuration as at least a portion of the structure coordinates of the OKT3 as set out in figure 5. In a preferred embodiment at least a portion of the structural coordinates of the molecule or molecular complex define the same relative spatial configuration as at least a portion of the coordinates of residues : Ser30, Tyr 31, Asp 49, Tφ90, and Ser91 of the light chain and Thr33, Tyr50, Asn52, Arg55, Tyr57, Lys74, Tyr99, AsplOl and Tyr 104 of the heavy chain of the OKT3 as set out in figure 5. In a most preferred embodiment at least a portion of the structure coordinates of the molecule or molecular complex define the same relative spatial configuration as the coordinates of a plurality of residues selected from the group consisting of : Ser30, Tyr 31, Asp 49, Tφ90, and Ser91 of the light chain and Thr33, Tyr50, Asn52, Arg55, Tyr57, Lys74, Tyr99, AsplOl and Tyr 104 of the heavy chain of the OKT3 as set out in figure 5. In another preferred embodiment at least a portion of the structural coordinates of the molecule or molecular complex define the same relative spatial configuration as at least a portion of the structure coordinates of the atoms of the OKT3 light and heavy chains identified in table 1 as being involved in binding of the OKT3 to CD3ε. Three-dimensional Data information provided by complexes As would be clear to a skilled addressee the importance of the information provided by crystallising a receptor and elucidating the structural relationship of the binding domain is that this information can be used in computer aided drug design applications. X-ray structure coordinates obtained when a crystal structure is solved define a unique configuration of three-dimensional points that serve to identify positions of the atoms in the crystal relative to each other. The data obtained does not, however, define an absolute set of points in space. As would be understood by a skilled addressee a set of structure coordinates for any crystal structure defines a relative set of points that, in turn, define a configuration of atoms in three dimensions. In essence the importance of crystal structure data is that it provides information as to the spatial relationship of the atoms in the crystal with respect to each other. It would be understood that a similar or identical configuration could just as easily be defined by an entirely different set of coordinates, provided the distances and angles between coordinates remained essentially the same. In addition, a scalable configuration of points can be defined by increasing or decreasing the distances between coordinates by a scalar factor while keeping the angles essentially the same. It is the relative information provided by the data set that is important in determining its utility for drug design applications not the absolute value of any of the data points obtained, r addition it should be noted that the crystal structure data obtained in figures 5 includes data pertaining to all atoms in the crystal When using this data in rational drug design only a portion of the structural coordinates are in fact needed as the important information is that detailing the relative conformation of the atoms constituting the binding site and/or point of interaction of the two molecules in the complex as the case may be. Thus a person could exploit the advance made by the applicant by only utilising a portion of the data and not the entire data set. For example by exploiting the data provided in figure 5 a skilled addressee could compile an abridged data set that when supplied to an appropriate computer program would provide all the information required to effectively model the binding domain. This would be sufficient to allow a skilled user to then use computer aided drug design programs, i general the data required relates to the binding domain identified by the crystal structure. Whilst the best drug design/modelling would be carried out using all the crystal data pertaining to the binding domain it is possible to use only a portion of the domain data and still get workable material. It is theoretically possible, therefore, that useful information could be obtained merely by including data from 2 points within the domain although the more points that are included the better the modelling will become. The present invention therefore includes within its scope data sets derived from the crystal structure data coordinates provided by the present invention or data sets defining the same relative spatial configuration of atoms as the structural coordinates of the crystal structure data provided by the present invention. As discussed above in most applications it is envisaged that only a portion of the data set will be needed. The invention therefore includes data sets where only a portion of the data set of the present invention is utilised, hi a preferred embodiment the data set includes data for at least 3 atoms derived from or defining the same relative spatial configuration as the data of the present invention. In a more preferred embodiment the data set includes 5 atoms, even more preferably 7 atoms, more preferably 11 atoms, even more preferably 20 atoms either derived from or defining the same relative structural configuration as the structural coordinates for atoms given in figure 5. The present invention therefore provides a data set defining a scalable three dimensional configuration of points at least a portion of said data set being derived from, or defining the same relative spatial configuration as, at least a portion of the structure coordinates of a CD3/OKT3 complex, hi a preferred embodiment at least a portion of the data is derived from or defines the same relative spatial configuration as at least a portion of the structure coordinates of a crystalline CD3/OKT3 complex as set out in figure 5. In one preferred embodiment at least a portion of the data in the data set is derived from or ' defines the same relative spatial configuration as at least a portion of the structural coordinates for amino acid residues Thr 12, Pro 13, Lys 15, Ser 17, Ser 19, Gly 20, Thr 21, Thr 22, He 24, Thr 26, Gln 29, Pro 31, Ser 33, Glu 34, Asn 40, Asp 41, Lys 42, Asn 43, Asp 47, Glu 48, Asp 49, Asp 50, Lys 51, Asn 52, Asp 56, Glu 57, Asp 58, His 59, Ser 61, Lys 63, Glu 64, Ser 66, Glu 67, Leu 68, Glu 69, Arg 79, Lys 82, Pro 83, Glu 84, Asp δ5, Asn δ7, Arg 95 of the epsilon chain of CD3εγ. In another preferred embodiment at least a portion of the data in the data set is derived from or defines the same relative spatial configuration as at least a portion of the structural coordinates for amino acids Glu 4δ, Asp 49, Asp 56, Glu 57, Asp 5δ, Glu 64, Glu 69 of the epsilon chain of CD3εγ. In another preferred embodiment at least a portion of the data in the data set is derived from or defines the same relative spatial configuration as at least a portion of the structural coordinates for amino acids Glu34, Gly46, Glu4δ, Arg79, GlyδO, Ser81, Lys82, Pro83, Asp 85 of the epsilon chain of CD3εγ as set out in figure 5. hi a more preferred embodiment the data set includes data which is derived from or defines the same relative spatial configuration as a plurality of these amino acid residues, preferably all these amino acid residues. In another preferred embodiment at least a portion of the data set is derived from or defines the same relative spatial configuration as at least a portion of the structure coordinates of the atoms of the CD3ε chain identified in table 1 as being involved in binding of the CD3εγ to OKT3. hi another preferred embodiment at least a portion of the data in the data set is derived from or defines the same relative spatial configuration as at least a portion of the structural coordinates for amino acid residues residues Gln 1, Ser 2, Lys 4, Asn 6, Tyr 12, Asp 13, Ala 14, Glu 16, Asp 17, Thr 23, Asp 25, Glu 27, Ala 28, Lys 29, Asp 36, Lys 38, Thr 44, Glu 45, Asp 46, Lys 47, Lys 48, Lys 49, Asn 51, Ser 54, Ala 56, Lys 57, Asp 58, Arg 60, Lys 66, Ser 68, Gln 69, Asn 70, Lys 71, Lys 73, Arg 80 of the gamma chain of CD3εγ. In another preferred embodiment at least a portion of the data in the data set is derived from or defines the same relative spatial configuration as at least a portion of the structural coordinates for amino acids residues Lys 35, Lys 38, Lys 57, Arg 60, Lys 66, Lys 71, Lys 73 of the gamma chain of CD3εγ. In another preferred embodiment at least a portion of the data in the data set is derived from or defines the same relative spatial configuration as at least a portion of the coordinates of Ser30, Tyr 31, Asp 49, Tφ90, and Ser91 of the light chain and Thr33, Tyr50, Asn52, Arg55, Tyr57, Lys74, Tyr99, AsplOl and Tyrl04 of the heavy chain of the OKT3 as set out in figure 5. In a more preferred embodiment the data set includes data derived from or defining the same relative spatial configuration as the coordinates of a plurality of these amino acid residues, preferably all of these amino acid residues. In another preferred embodiment at least a porion of the structural coordinates of the data set are derived from or define the same relative spatial configuration as at least a portion of the structure coordinates of the atoms of the OKT3 light and heavy chain identified in table 1 as being involved in binding of the OKT3 to CD3ε. The data sets referred to above can be used to generate a scalable 3-dimensional set of points. The present invention therefore includes within its scope scalable 3-dimensional sets of points derived from the crystal structure data coordinates provided by the present invention or scalable 3-dimensional sets of points defining the same relative spatial configuration of atoms as the structural coordinates of the crystal structure data provided by the present invention. As discussed above in most applications it is envisaged that only a portion of the points will be needed. The invention therefore includes sets of points where only a portion of the points of the present invention are utilised. In a preferred embodiment the set of points includes point for at least 3 atoms derived from or defining the same relative spatial relationship as the point of the present invention. In a more preferred embodiment the data set includes 5 atoms, even more preferably 7 atoms, more preferably 11 atoms, even more preferably 20 atoms either derived from or defining the same relative spatial configuration as the points defined by the structural coordinates in figures 5. In one preferred embodiment invention provides a scalable three dimensional configuration of points, at least a portion of the points being derived from, or defining the same relative spatial configuration as, at least a portion of the structure coordinates of a CD3/OKT3 complex. In a preferred embodiment at least a portion of the data is derived from or defines the same relative spatial configuration as at least a portion of the structure coordinates of a crystalline CD3/OKT3 complex as set out in figure 5. In one preferred embodiment at least a portion of the points is derived from or defines the same relative spatial configuration as at least a portion of the structural coordinates of amino acid residues Thr 12, Pro 13, Lys 15, Ser 17, Ser 19, Gly 20, Thr 21, Thr 22, He 24, Thr 26, Gln 29, Pro 31, Ser 33, Glu 34, Asn 40, Asp 41, Lys 42, Asn 43, Asp 47, Glu 48, Asp 49, Asp 50, Lys 51, Asn 52, Asp 56, Glu 57, Asp 58, His 59, Ser 61, Lys 63, Glu 64, Ser 66, Glu 67, Leu 68, Glu 69, Arg 79, Lys 82, Pro 83, Glu 84, Asp 85, Asn 87, Arg 95 of the epsilon chain of CD3εγ. In another preferred embodiment at least a portion of the points is derived from or defines the same relative spatial configuration as at least a portion of the structural coordinates for amino acids Glu 4δ, Asp 49, Asp 56, Glu 57, Asp 58, Glu 64, Glu 69 of the epsilon chain of CD3εγ. In another preferred embodiment at least a portion of the points are derived from or defines the same relative spatial configuration as at least a portion of the structural coordinates for amino acids Glu34, Gly46, Glu48, Arg79, GlyδO, Serδl, Lys82, Proδ3, Asp δ5 of CD3εγ as set out in figure 5. In a more preferred embodiment the set of points includes points which are derived from or defines the same relative spatial configuration as a plurality of these amino acid residues, preferably all these amino acid residues. In another preferred embodiment at least a portion of the points are derived from or define the same relative spatial configuration as at least a portion of the structure coordinates of the atoms of the CD3ε chain identified in table 1 as being involved in binding of the CD3εγ to OKT3. i another preferred embodiment at least a portion of the points are derived from or defines the same relative spatial configuration as at least a portion of the structural coordinates for amino acid residues residues Gln 1, Ser 2, Lys 4, Asn 6, Tyr 12, Asp 13, Ala 14, Glu 16, Asp 17, Thr 23, Asp 25, Glu 27, Ala 28, Lys 29, Asp 36, Lys 38, Thr 44, Glu 45, Asp 46, Lys 47, Lys 48, Lys 49, Asn 51, Ser 54, Ala 56, Lys 57, Asp 58, Arg 60, Lys 66, Ser 68, Gln 69, Asn 70, Lys 71, Lys 73, Arg 80 of the gamma chain of CD3εγ. In another preferred embodiment at least a portion of the points are derived from or defines the same relative spatial configuration as at least a portion of the structural coordinates for amino acids residues Lys 35, Lys 38, Lys 57, Arg 60, Lys 66, Lys 71, Lys 73 of the gamma chain of CD3εγ. In yet another preferred embodiment at least a portion of the points is derived from or defines the same relative spatial configuration as the coordinates of Ser30, Tyr 31, Asp 49, Tφ90, and Ser91 of the light chain and Thr33, Tyr50, Asn52, Arg55, Tyr57, Lys74, Tyr99, AsplOl and Tyrl04 of the heavy chain of the OKT3 as set out in figure 5. The configurations of points in space derived from structure coordinates according to the invention can be visualized as, for example, a holographic image, a stereodiagram, a model or a computer-displayed image, and the invention thus includes such images, diagrams or models. Structurally Equivalent Crystal Structures There are a number of computational analytical techniques that can be used to determine whether a molecule or a substrate binding domain portion thereof is "structurally equivalent," defined in terms of its three-dimensional structure, to all or part of the CD3εγ binding domain or a complex thereof. These techniques may be carried out in current software applications, such as for example the Molecular Similarity application of QUANTA (Molecular Simulations hie, San Diego, CA) version 4.1. Whilst each individual application that allows these calculations to be carried out works on slightly different principles. The end use output is typically very similar for each application. The Molecular Similarity application permits comparisons between different structures, different conformations of the same structure, and different parts of the same structure. The procedure used in Molecular Similarity to compare structures is divided into four steps: 1) load the structures to be compared; 2) define the atom equivalences in these structures; 3) perform a fitting operation; and 4) analyze the results. Each structure is identified by a name. One structure is identified as the target (ie., the fixed structure); all remaining structures are working structures (ie., moving structures). When a rigid fitting method is used, the working structure is translated and rotated to obtain an optimum fit with the target structure. The fitting operation uses a least squares fitting algorithm which computes the optimum translation and rotation to be applied to the moving structure, such that the root mean square difference of the fit over the specified pairs of equivalent atom is an absolute minimum. This number, given in angstroms, is reported by QUANTA. As used herein, any molecule or molecular complex or substrate binding domain thereof, or any portion thereof, that has a root mean square deviation of conserved residue backbone atoms (N, Ca, C, 0) of less than about 2.1 A, when superimposed on the relevant backbone atoms described by the reference structure coordinates listed in Figures 5, is considered "structurally equivalent" to the reference molecule, hi other words, the crystal structures of those portions of the two molecules are substantially identical, within acceptable error margins typically observed. Particularly preferred structurally equivalent molecules or molecular complexes are those that are defined by the entire set of structure coordinates listed in Figure 5 ± a root mean square deviation from the conserved backbone atoms of those amino acids of not more than 2.1 Angstrom. More preferably, the root mean square deviation is less than about 1.0 Angstrom. The invention thus further provides a machine-readable storage medium comprising a data storage means encoded with machine readable data which, when using a machine programmed with instructions for reading and utilising the data, is capable of displaying a graphical three- dimensional representation of any of the molecule or molecular complexes of the invention. In a preferred embodiment, the machine-readable data storage medium comprises a data storage material encoded with machine readable data which, when using a machine programmed with instructions for using said data, is capable of displaying a graphical three-dimensional representation of a all or part of the CD3εγ/OKT3 complex. In another preferred embodiment, the machine-readable data storage medium comprises a data storage material encoded with machine readable data which, when using a machine programmed with instructions for using said data, is capable of displaying a graphical three-dimensional representation of a molecule or molecular complex defined by_. the structure coordinates of all or some of the amino acids listed in Figures 5, ± a root mean square deviation from the backbone atoms of said amino acids of not more than 2.1 Angstrom. In an alternative embodiment, the machine-readable data storage medium comprises a data storage material encoded with a first set of machine readable data which comprises the Fourier transform of the structure coordinates set forth in Figure 5, and which, when using a machine programmed with instructions for using said data, can be combined with a second set of machine readable data comprising the x-ray diffraction pattern of a molecule or molecular complex to determine at least a portion of the structure coordinates corresponding to the second set of machine readable data. As would be clear to a skilled addressee a suitable system for reading a data storage means may include a computer device comprising a central processing unit ("CPU"), a working memory which may be, e.g., RAM (random access memory) or 1 lcorelf memory, mass storage memory (such as one or more disk drives or CD-ROM drives), one or more display devices (e.g., cathode-ray tube ("CRT") displays, light emitting diode ("LED") displays, liquid crystal displays (TCDs"), electroluminescent displays, vacuum fluorescent displays, field emission displays (TEDs"), plasma displays, projection panels, etc.), one or more user input devices (e.g., keyboards, microphones, mice, track balls, touch pads, etc.), one or more input lines, and one or more output lines, all of which are interconnected by a conventional bidirectional system bus. The system may be a stand-alone computer, or may be networked (e.g., through local area networks, wide area networks, intranets, extranets, or the internet) to other systems (e.g., computers, hosts, servers, etc.). The system may also include additional computer controlled devices such as consumer electronics and appliances. The systems described above may also be provided with input and output means for the importing and exporting of data to and from the computer. Input means may be coupled to the computer by any of a variety of well known methods. Machine-readable data may be imported using a modem or modems connected by any suitable data line. Alternatively or additionally, the input hardware may comprise CD-ROM drives or disk drives. In essence any known input device can be used. Output means may be coupled to the computer by output lines and may similarly be implemented by conventional devices. The output means may include a display device for displaying a graphical representation of a binding pocket of this invention using a computer program. The output means may also include a printer, so that hard copy output may be produced, or a disk drive, to store system output for later use. In operation, a CPU coordinates the use of the various input and output means, coordinates data accesses from mass storage devices, accesses to and from working memory, and determines the sequence of data processing steps. A number of programs may be used to process the machine-readable data of this invention. Such programs are discussed in reference to the computational methods of drug discovery discussed below. References to components of the hardware system are included as appropriate throughout the following description of the data storage medium. Machine-readable storage devices useful in the present invention include, but are not limited to, magnetic devices, electrical devices, optical devices, and combinations thereof. Data storage devices include, but are not limited to, hard disk devices, CD devices, digital video disk devices, floppy disk devices, removable hard disk devices, magneto-optic disk devices, magnetic tape devices, flash memory devices, bubble memory devices, holographic storage devices, and any other mass storage peripheral device. It should be understood that these storage devices include necessary hardware (e.g., drives, controllers, power supplies, etc.) as well as any necessary media (e.g., disks, flash cards, etc.) to enable the storage of data. Rational Drug Design Traditionally drug development and design has occurred by pharmaceutical companies undertaking large screening programs, by the use of structure activity studies or by serendipity. Whilst these techniques are successful to a point they are labour intensive and rely on luck and the breadth of the study rather than rigorous principles of the desired interaction at a molecular level. More recently drug design has been carried out by using computer assisted models which can model the desired interaction hopefully leading to improved therapeutic compounds. Computers therefore provide the drug developer with the ability to screen, identify, select and/or design chemical entities capable of associating the particular receptor of interest. As would be clear, however, before this can be carried out detailed knowledge of the structure of the receptor must be known so that this data can be input into the computer software that carries out the modelling. Whilst it is theoretically possible with certain applications to predict the confirmation of the receptor using energy minimisation models these are only accurate to a point. Detailed knowledge of the exact structural coordinates of a receptor permits the design and/or identification of synthetic compounds and/or other molecules which are spatially adapted for optimal interaction with the binding site of the receptor. Accordingly computer aided drug design can be used to identify or design chemical entities, such as inhibitors, agonists and antagonists, that associate the CD3εγ binding domain. Inhibitors may bind to or interfere with all or a portion of an active site the domain. Once identified and screened for biological activity, these inhibitors/agonists/antagonists may be used therapeutically or prophylactically to block the receptor and therefore should be useful in preventing transplant rejection and the treatment of autoimmune conditions. Chemical entities that are identified or designed by computer methods to interact with the CD3εγ receptor are potential inhibitors of the receptor and are therefore potential drug candidates. It is therefore possible to identify potential agonists and antagonists to the CD3εγ binding domain by consideration of the X-Ray crystallography data. Such data can be used in computational methods well known in the art to determine which residues are on the surface of a receptor molecule and therefore potentially able to interact with other molecules in solution, hi general these techniques rely on graphic representations of the receptor and computer assisted manipulation of the graphic representation. The structural coordinate data stored in a machine-readable storage medium that is capable of displaying a graphical three-dimensional representation of the structure of a receptor binding domain or portion thereof in a liganded and unliganded state can therefore be used in drug discovery. The structure coordinates of the chemical entity are used to generate a three- dimensional image that, can be computationally fitted to the three-dimensional image of CD3εγ . The data can be used by a number of well known programs to display the structure of the region of interest. There are a number of computer programs that can be used to do this with well known examples including BUSTER, CHAIN, CCP4, DIANA, FELLX, FRODO, HKL, HEAVY, MADIGRAS, MOSFILM, PHASES, O, RASMOL, SHARP, SOLVE, XDS and XPLOR merely to name a few. The process of rational drug described above is considered by the applicants of the present invention to be well known to skilled addressees in this area and it is felt that the description given above would be sufficient to explain the process to a skilled addressee. Nevertheless in order to assist a lay reader we provide a brief description of computational design intended to detail how the data provided by the present invention can be utilised in this process. Various computational analyses are can be used to determine whether a molecule is sufficiently complementary to the target moiety or structure to be useful as a pharmaceutical agent. Such analyses may be carried out in current software applications, such as the Molecular Similarity application of QUANTA (Molecular Simulations Inc., Waltham, Mass.) version 3.3, and as described in the accompanying User's Guide, Volume 3 pages 134-135. Other well known program include CAVEAT, CHARM, CHAIN, CATALYST, DOCK, FRODO, INSIGHT, ISIS, LEAPFROG, MODELLER< MCSS/HOOK, O, and RASMOL to name but a few. The Molecular Similarity application permits comparisons between different structures, different conformations of the same structure, and different parts of the same structure. The procedure used in Molecular Similarity to compare structures is divided into four steps: 1) load the structures to be compared; 2) define the atom equivalences in these structures; 3) perform a fitting operation; and 4) analyze the results. Each structure is identified by a name. One structure is identified as the target (ie., the fixed structure); all remaining structures are working structures (ie., moving structures). When a rigid fitting method is used, the working structure is translated and rotated to obtain an optimum fit with the target structure. The fitting operation uses a least squares fitting algorithm which computes the optimum translation and rotation to be applied to the moving structure, such that the root mean square difference of the fit over the specified pairs of equivalent atom is an absolute minimum. This number, given in angstroms, is reported by QUANTA. One skilled in the art may use one of several methods to screen chemical entities or fragments for their ability to associate with a target site. Again, these methods require no elucidation for the skilled person, but are described here for the benefit of the unskilled reader. The screening process begins by visual inspection of the target site on the computer screen, generated from a machine-readable storage medium. Selected fragments or chemical entitles may then be positioned in a variety of orientations, or docked, within that binding pocket as defined above. Docking may be accomplished using software such as Quanta and Sybyl, followed by energy minimization and molecular dynamics with standard molecular mechanics force fields, such as CHARMM and AMBER. Specialized computer programs may also assist in the process of selected fragments or chemical entities. These include:

1. GRID (Goodford, 1985). GRID is available from Oxford University, Oxford, UK.

2. MCSS (Miranker et al., 1991). MCSS is available from Molecular Simulations, Burlington, Mass. 3. AUTODOCK (Goodsell, 1990). AUTODOCK is available from Scripps Research

Institute, La Jolla, Calif.

DOCK (Kuntz, 1982). DOCK is available from University of California, San Francisco,

Calif. Once suitable chemical entities or fragments have been selected, they can be assembled into a single compound or complex. Assembly may be preceded by visual inspection of the relationship of the fragments to each other on the three-dimensional image displayed on a computer screen in relation to the structure coordinates of the target compound or site. This would be followed by manual model building using software such as Quanta or Sybyl. Useful programs to aid one of skill in the art in connecting the individual chemical entities or fragments include:

1. CAVEAT (Bartlett, 1989). CAVEAT is available from the University of

California, Berkeley, Calif. 2. 3D Database systems such as MACCS-3D (MDL Information Systems, San

Leandro, Calif). This area is reviewed by Martin (1992).

HOOK (available from Molecular Simulations Burlington, Mass.). As the skilled reader will already know, instead of proceeding to build a ligand for the target in a step-wise fashion, one fragment or chemical entity at a time as described above, target-binding compounds may be designed as a whole or de novo. These methods include:

1. LUDI (Bohm, 1992). LUDI is available from the Biosym Technologies, San Diego, Calif.

2. LEGEND (Nishibata, 1991). LEGEND is available from Molecular Simulations, Burlington, Mass.

3. LeapFrog (available from Tripos Associates, St. Louis. Mo.). Other molecular modelling tecliniques may also be employed. See for example Cohen (1990). See also Navia (1992). Once a compound has been designed or selected by such methods, the efficiency with which that compound can bind to a target site may be tested and optimised by computational evaluation. For example, an effective ligand will preferably demonstrate a relatively small difference in energy between its bound and free states, ie. a small deformation energy of binding. Thus the most efficient ligand should preferably be designed with a deformation energy of binding of not greater than about lOkcal/mole, preferably, not greater than 7 kcal/mole. Ligands may interact with the target in more than one conformation that is similar in overall binding energy. In those cases, the deformation energy of binding is taken to be the difference between the energy of the free entity and the average energy of the conformations observed when the inhibitor binds to the protein. An entity designed or selected as binding to a target may be further computationally optimised so that in its bound states it would preferably lack repulsive electrostatic interaction with the target enzyme. Such non-complementary (e.g., electrostatic) interactions include repulsive charge-charge, dipole-dipole and charge-dipole interactions. Specifically, the sum of all electrostatic interactions between the ligand and the target, when the ligand is bound to the target, preferably makes a neutral or favourable contribution to the enthalpy of binding. Specific computer software is available in the art to evaluate compound deformation energy and electrostatic interaction. Examples of programs designed for such uses include: Gaussian 92, revision C [M.J. Frisch, Gaussian, hie, Pittsburgh, Pa. COPYRGT. 1992]; AMBER, version 4.0 [P.A. Kol nan, University of California at San Francisco, COPYRGT.1994]; QUANTA/CHARMM [Molecular Simulations, hie, Burlington, Mass. COPYRGT.1994]; and Insight H/Discover (Biosysm Technologies hie, San Diego, Calif. COPYRGT.1994). These programs may be implemented, for instance, using a Silicon Graphics workstation, IRIS 4D/35 or IBM RISC/6000 workstation model 550. Other hardware systems and software packages will be known to those skilled in the art. Once the ligand has been optimally selected or designed, as described above, substitutions may then be made in some of its atoms or side groups in order to improve or modify its binding properties. Generally initial substitutions are conservative, ie., the replacement group will have approximately the same size, shape, hydrophobicity and charge as the original group. It should, of course, be understood that components known in the art to alter conformation should be avoided. Such substituted chemical compounds may then be analysed for efficiency of fit to the desired target site by the same computer methods described in detail, above. Again, all these facts are familiar to the skilled person. Another approach is the computational screening of small molecule data bases for chemical entities or compounds which can bind in whole, or in part, to a desired target. In this screening, the quality of fit of such entities to the binding site may be judged either by shape complementarity or by estimated interaction energy. (Meng, 1992). The computational analysis and design of molecules, as well as software and computer systems therefor, are described in U.S Patent No. 5,978,740 which is included herein by reference, including specifically but not by way of hmitation the computer system diagram described with reference to and illustrated in Figure 3 thereof, as well as the data storage media diagram described with reference to and illustrated in Figure 4s and 5 thereof. Pursuant to the present invention, such stereochemical complementarity is characteristic of a molecule which matches intra-site surface residues lining the binding regions identified herein. By "match" we mean that the identified portions interact with the surface residues, for example, via hydrogen bonding or by enthalpy/entropy-reducing van der Waals interactions which promote desolvation of the biologically active compound within the site, in such a way that retention of the biologically active compound within the groove is energetically favoured. It will be appreciated that it is not necessary that the complementarity between ligands and the substrate/ligand binding site extend over all residues lining the site in order to inhibit stabilise binding of the natural ligand. Accordingly, ligands which bind to some, but not all, of the residues lining the site are encompassed by the present invention. In general, the design of a molecule possessing stereochemical complementarity can be accomplished by means of techniques which optimise, either chemically or geometrically, the "fit" between a molecule and a target receptor. Suitable such techniques are known in the art. (See Sheridan and Venkataraghavan, 1987; Goodford 1984; Beddell 1985; Hoi, 1986; and Verlinde 1994, the respective contents of which are hereby incoφorated by reference. See also Blundell 1987). Thus there are two preferred approaches to designing a molecule according to the present invention, which complements the shape of the binding sites. In the first of these, the geometric approach, the number of internal degrees of freedom, and the corresponding local minima in the molecular conformation space, is reduced by considering only the geometric (hard-sphere) interactions of two rigid bodies, where one body (the active site) contains "pockets" or "grooves" which form binding sites for the second body (the complementing molecule, as ligand). The second approach entails an assessment of the interaction of different chemical groups ("probes") with the active site at sample positions within and around the site, resulting in an array of energy values from which three- dimensional contour surfaces at selected energy levels can be generated. The geometric approach is illustrated by Kuntz et al. (19δ2), the contents of which are hereby incoφorated by reference, whose algorithm for ligand design is implemented in a commercial software package distributed by the Regents of the University of California and further described in a document, provided by the distributor, entitled "Overview of the DOCK Package, Version 1.0,", the contents of which are hereby incoφorated by reference. Pursuant to the Kuntz algorithm, the shape of the cavity represented by the substrate/ligand binding site is defined as a series of overlapping spheres of different radii. One or more extant databases of crystallographic data, such as the Cambridge Structural Database System maintained by Cambridge University (University Chemical Laboratory, Lensfield Road, Cambridge CB2 1EW, U.K.) and the Protein Data Bank maintained by the Research Collaboratory for Structural Bioinformatics (RCSB; http//www.rcsb.org/index.html) is then searched for molecules which approximate the shape thus defined. Molecules identified in this way, on the basis of geometric parameters, can then be modified to satisfy criteria associated with chemical complementarity, such as hydrogen bonding, ionic interactions and van der Waals interactions. The chemical-probe approach to ligand design is described, for example, by Goodford (19δ5), the contents of which are hereby incoφorated by reference, and is implemented in several commercial software packages, such as GRID (product of Molecular Discovery Ltd., West Way House, Elms Parade, Oxford OX2 9LL, U.K.). Pursuant to this approach, the chemical prerequisites for a site-complementing molecule are identified at the outset, by probing the substrate/ligand binding site with different chemical probes, e.g., water, a methyl group, an amine nitrogen, a carboxyl oxygen, and a hydroxyl. Favoured sites for interaction between the active site and each probe are thus determined, and from the resulting three-dimensional pattern of such sites a putative complementary molecule can be generated. Programs suitable for searching three-dimensional databases to identify molecules bearing a desired pharmacophore include: MACCS-3D and ISIS/3D (Molecular Design Ltd., San Leandro, CA), ChemDBS-3D (Chemical Design Ltd., Oxford, U.K.), and Sybyl/3DB Unity (Tripos Associates, St. Louis, MO). Programs suitable for pharmacophore selection and design include: DISCO (Abbott

Laboratories, Abbott Park, EL), Catalyst (Bio-CAD Coφ., Mountain View, CA), and ChemDBS-3D (Chemical Design Ltd., Oxford, U.K.). Databases of chemical structures are available from a number of sources including Cambridge Crystallographic Data Centre (Cambridge, U.K.) and Chemical Abstracts Service (Columbus, OH). De novo design programs include Ludi (Biosym Technologies Inc., San Diego, CA), Sybyl (Tripos Associates) and Aladdin (Daylight Chemical Information Systems, Irvine, CA). Those skilled in the art will recognize that the design of a mimetic compound may require slight structural alteration or adjustment of a chemical structure designed or identified using the methods of the invention. This aspect of the invention may be implemented in hardware or software, or a combination of both. However, the invention is preferably implemented in computer programs executing on programmable computers each comprising a processor, a data storage system (including volatile and non-volatile memory and/or storage elements), at least one input device, and at least one output device. Program code is applied to input data to perform the functions described above and generate output information. The output information is applied to one or more output devices, in known fashion. The computer may be, for example, a personal computer, microcomputer, or work station of conventional design. Each program is preferably implemented in a high level procedural or object- oriented programming language to communicate with a computer system. However, the programs can be implemented in assembly or machine language, if desired. In any case, the language may be compiled or inteφreted language. Each such computer program is preferably stored on a storage medium or device (e.g., ROM or magnetic diskette) readable by a general or special puφose programmable computer, for configuring and operating the computer when the storage media or device is read by the computer to perform the procedures described herein. The inventive system may also be considered to be implemented as a computer-readable storage medium, configured with a computer program, where the storage medium so configured causes a computer to operate in a specific and predefined manner to perform the functions described herein. Compounds identified by the methods of the present invention may be assessed by a number of in vitro and in vivo assays. For example, binding affinity for candidate ligands may be measured using biosensor technology. A compound identified by the methods described herein may be subsequently subjected to in vitro and/or in vivo testing for ability to act as an antagonist/agonist of binding of natural substrates and/or co-factors and/or interactors of CD3. Useful compounds will have the ability to interact with the binding domain of CD3 in such a way that the binding of a natural substrate and/or co-factor and/or interactor is either enhanced or reduced. The agonist and antagonist compounds of the present invention are not limited to antibodies reactive to the protein-binding domain or any portions thereof and which compete with the binding of substrate and/or co-factor and/or interactor. Other compounds including small molecules or synthetic or natural chemical compounds capable of competing with the binding of a substrate and/or co-factor and/or interactor to the binding domain or any portion thereof are also included in the present invention. The invention therefore provides a method of using the data generated to identify and/or design agents that are capable of binding to the binding domain of the CD3 and hence act as agonists or antagonists of the receptor. The present invention therefore also provides a method of an agent which is capable of acting as a ligand of CD3εγ the method including the step of identifying an agent that has a conformation and/or polarity such that it is capable of interacting with at least one relevant amino acid residue or portion thereof of the CD3εγ. The present invention therefore also provides a method of identifying an agent which is capable of bonding to CD3εγ the method including the step of identifying an agent that has a conformation and/or polarity such that it is capable of interacting with at least one relevant amino acid residue or portion thereof of the CD3εγ. hi a preferred embodiment the method includes the step of identifying an agent that has a conformation and/or polarity such that it is capable of interacting with one or more amino acid residues selected from the group consisting of: Thr 12, Pro 13, Lys 15, Ser 17, Ser 19, Gly 20, Thr 21, Thr 22, He 24, Thr 26, Gln 29, Pro 31, Ser 33, Glu 34, Asn 40, Asp 41, Lys 42, Asn 43, Asp 47, Glu 48, Asp 49, Asp 50, Lys 51, Asn 52, Asp 56, Glu 57, Asp 58, His 59, Ser 61, Lys 63, Glu 64, Ser 66, Glu 67, Leu 68, Glu 69, Arg 79, Lys 82, Pro 83, Glu 84, Asp 85, Asn 87, Arg 95 of the epsilon chain of CD3εγ. In another preferred embodiment the method includes the step of identifying an agent that has a conformation and/or polarity such that it is capable of interacting with one or more amino acid residues selected from the group consisting of amino acids Glu 48, Asp 49, Asp 56, Glu 57, Asp 58, Glu 64, Glu 69 of the epsilon chain of CD3εγ. h another preferred embodiment the method includes the step of identifying an agent that has a conformation and/or polarity such that it is capable of interacting with one or more amino acid residues selected from the group consisting of amino acids Glu34, Gly46, Glu48, Arg79, GlyδO, Serδl, Lys82, Pro83, Asp δ5 of the epsilon chain of CD3εγ. In a more preferred embodiment agent interacts with a as a plurality of these amino acid residues, preferably all these amino acid residues, hi another preferred embodiment the method includes the step of an identifying agent that has a conformation and/or polarity such that it is capable of interacting with one or more of the atoms of the CD3ε chain identified in table 1 as being involved in binding of the CD3εγ to OKT3. In a most preferred embodiment the method includes the step of identifying an agent that is capable of interacting with a plurality of atoms of the CD3ε chain identified in table 1, preferably all the atoms of the CD3ε chain identified in table 1. In another preferred embodiment the method includes the step of identifying an agent that has a conformation and/or polarity such that it is capable of interacting with one or more amino acid residues selected from the group consisting Gln 1, Ser 2, Lys 4, Asn 6, Tyr 12, Asp 13, Ala 14, Glu 16, Asp 17, Thr 23, Asp 25, Glu 27, Ala 2δ, Lys 29, Asp 36, Lys 38, Thr 44, Glu 45, Asp 46, Lys 47, Lys 48, Lys 49, Asn 51, Ser 54, Ala 56, Lys 57, Asp 58, Arg 60, Lys 66, Ser 68, Gln 69, Asn 70, Lys 71, Lys 73, Arg 80 of the gamma chain of CD3εγ. In another preferred embodiment the method includes the step of identifying an agent that has a conformation and or polarity such that it is capable of interacting with one or more amino acid residues selected from the group consisting of Lys 35, Lys 38, Lys 57, Arg 60, Lys 66, Lys 71, Lys 73 of the gamma chain of CD3εγ. hi the methods it is preferred that the agent interacts with a plurality of these residues, preferably at least 3, more preferably at least 5, even more preferably at least 7, even more preferably at least 9, most preferably all of these residues. Of course the method can be carried out in a number of ways such as by hand held modelling and manual transcription techniques (such as depicting the model on a blackboard, for example. It is preferred that the method involves computer assisted modelling. In a most preferred embodiment the agent has the ability to interact with these residues when they are in the conformation adopted by the corresponding amino acids in figure 5. It is preferred that the method is implemented in hardware or software, or a combination of both. Preferably the method is implemented in computer programs executing on programmable computers each comprising a processor, a data storage system including volatile and non-volatile memory and/or storage elements, at least one input device, and at least one output device. It is also preferred that the computer program is implemented in a high level procedural or object-oriented programming language to communicate with a computer system. Even more preferably the computer program is stored on a storage medium or device readable by a general or special purpose programmable computer, for configuring and operating the computer when the storage media or device is read by the computer to perform a method according to the invention. hi one embodiment the method is carried out using in vitro and/or in vivo assays. Preferably the assay is selected from the group consisting of binding assay, competition binding assay, crystallisation assays, biosensor assay and X-Ray crystallography. In yet a further aspect there is provided a computer-assisted method for identifying an agent capable of binding to the binding domain of a CD3εγ including the steps of:

(a) supplying a computer modelling application with a set of structure coordinates of a molecule or molecular complex, at least a portion of the structural coordinates of the molecule or molecular complex being derived from, or defining the same relative spatial configuration as, at least a portion of the atomic coordinates of a CD3εγ binding domain as set out in figure 5;

(b) supplying the computer modelling application with a set of structure coordinates an agent; and (c) determining whether the agent is expected to bind to the molecule or molecular complex, wherein binding to the molecule or molecular complex is indicative of binding to the CD3εγ. The step of supplying the computer with a set of structure coordinates of an agent typically involves provision of the coordinates from a chemical library of compounds. In a particularly preferred embodiment the agent thus identified is then screened using a biological assay to determine if the compound binds to the CD3εγ in vivo and /or in vitro. In yet an even further aspect there is provided a computer-assisted method for designing an agent capable of binding to the binding domain of a CD3εγ including the steps of: (a) supplying a computer modelling application with a set of structure coordinates of a molecule or molecular complex, at least a portion of the structural coordinates of the molecule or molecular complex being derived from, or defining the same relative spatial configuration as, at least a portion of the atomic coordinates of a CD3εγ binding domain as set out in figure 5; (b) supplying the computer modelling application with a set of structure coordinates for an agent;

(c) evaluating the potential binding interactions between the agent and substrate binding pocket of the molecule or molecular complex; (d) structurally modifying the agent to yield a set of structure coordinates for a modified agent; and

(e) determining whether the modified agent is expected to bind to the molecule or molecular complex, wherein binding to the molecule or molecular complex is indicative of a potential ligand of CD3εγ. In a particularly preferred embodiment the agent thus designed is then screened using a biological assay to determine if the agent binds to the CD3εγ in vivo and /or in vitro. hi yet an even further aspect the invention provides a computer-assisted method for designing an agent capable of binding to a CD3εγ including: (a) supplying a computer modelling application with a set of structure coordinates of a molecule or molecular complex, at least a portion of the structural coordinates of the molecule or molecular complex being derived from, or defining the same relative spatial configuration as, at least a portion of the atomic coordinates of the CD3εγ binding domain as set out in figure 5; (b) computationally building a model of an agent represented by set of structure coordinates; and

(c) determining whether the agent is expected to bind to the molecule or molecular complex, wherein binding to the molecule or molecular complex is indicative of potential binding to the CD3εγ. The step of supplying the computer with a set of structure coordinates of an agent typically involves provision of the coordinates from a chemical library of compounds. In a particularly preferred embodiment the agent thus identified/desired is then screened using a biological assay to determine if the compound binds to the CD3εγ in vivo and /or in vitro. In an even more preferred embodiment the step of determining whether the agent is expected to bind to the molecule or molecular complex includes performing a fitting operation between the agent and a binding pocket of the molecule or molecular complex, followed by computationally analysing the results of the fitting operation to quantify the association between the agent and the binding pocket. A particularly preferred embodiment of the method involves screening a library of potential agents. In each of the three above identified methods there is a step of supplying the structure coordinates of a binding domain of CD3εγ derived from figure 5. In relation to this step there are a number of preferred binding domains that can be used in the methods. In one preferred embodiment the binding domain includes at least one amino acid selected from the group consisting of: Thr 12, Pro 13, Lys 15, Ser 17, Ser 19, Gly 20, Thr 21, Thr 22, He 24, Thr 26, Gln 29, Pro 31, Ser 33, Glu 34, Asn 40, Asp 41, Lys 42, Asn 43, Asp 47, Glu 48, Asp 49, Asp 50, Lys 51, Asn 52, Asp 56, Glu 57, Asp 58, His 59, Ser 61, Lys 63, Glu 64, Ser 66, Glu 67, Leu 68, Glu 69, Arg 79, Lys 82, Pro 83, Glu 84, Asp 85, Asn 87, Arg 95 of the epsilon chain of CD3εγ. Another preferred domain within this domain includes at least one amino acid selected from the group consisting of Glu 48, Asp 49, Asp 56, Glu 57, Asp 58, Glu 64, Glu 69 of the epsilon chain of CD3εγ. Another preferred domain on the epsilon chain includes one or more amino acid residues selected from the group consisting of residues Glu34, Gly46, Glu48, Arg79, GlyδO, Serδl, Lysδ2, Proδ3, Asp δ5 of the epsilon chain of CD3εγ. hi a most preferred domain the chain includes the atoms of the CD3ε chain identified in table 1 as being involved in binding. In a further preferred embodiment the binding domain used in the method includes at least one amino acid selected from the group consisting of: Gln 1, Ser 2, Lys 4, Asn 6, Tyr 12, Asp 13, Ala 14, Glu 16, Asp 17, Thr 23, Asp 25, Glu 27, Ala 28, Lys 29, Asp 36, Lys 38, Thr 44, Glu 45, Asp 46, Lys 47, Lys 48, Lys 49, Asn 51, Ser 54, Ala 56, Lys 57, Asp 58, Arg 60, Lys 66, Ser 68, Gln 69, Asn 70, Lys 71, Lys 73, Arg 80 of the gamma chain of CD3εγ. A particularly preferred domain within this binding domain includes at least one amino acid selected from the group consisting of Lys 35, Lys 38, Lys 57, Arg 60, Lys 66, Lys 71, Lys 73 of the gamma chain of CD3εγ. In a preferred embodiment the step of determining whether the modified chemical entity is expected to bind to or interfere with the molecule or molecular complex includes performing a fitting operation between the agent and a binding pocket of the molecule or molecular complex, followed by computationally analysing the results of the fitting operation to quantify the association between the agent and the binding pocket. In an even more preferred embodiment of the method the set of structure coordinates for the agent is obtained from a chemical fragment library. In yet a further aspect there is provided a computer-assisted method for identifying an agent capable of binding to the binding domain of a CD3εγ including the steps of: (a) supplying a computer modelling application with a set of structure coordinates of a molecule or molecular complex, at least a portion of the structural coordinates of the molecule or molecular complex being derived from, or defining the same relative spatial configuration as, at least a portion of the atomic coordinates Ser30, Tyr 31, Asp 49, Tφ90, and Ser91 of the light chain and Thr33, Tyr50, Asn52, Arg55, Tyr57, Lys74, Tyr99, AsplOl and Tyrl04 of the heavy chain of the OKT3 as set out in figure 5; (b) supplying the computer modelling application with a set of structure coordinates of an agent; and (c) computationally determining the structural similarity of the agent with the molecule or molecular complex, wherein a high level of structural similarity of agent with the molecule or molecular complex is indicative of potential binding to the CD3εγ. In yet an even further aspect there is provided a computer-assisted method for designing a ligand of CD3εγ including: (a) supplying a computer modelling application with a set of structure coordinates of a molecule or molecular complex, at least a portion of the structural coordinates of the molecule or molecular complex being derived from, or defining the same relative spatial configuration as, at least a portion of the atomic coordinates Ser30, Tyr 31, Asp 49, Tφ90, and Ser91 of the light chain and Thr33, Tyr50, Asn52, Arg55, Tyr57, Lys74, Tyr99, AsplOl and Tyrl04. of the heavy chain of the OKT3 as set out in figure 5,

(d) structurally modifying the chemical entity to increase the level of structural similarity of the agent with the molecule or molecular complex to yield a set of structure coordinates for a modified agent, hi a preferred embodiment of the method steps (c) and (d) are conducted a plurality of times. hi yet an even further aspect the invention provides a computer-assisted method for designing an agent capable of binding to CD3εγ including:

(a) supplying a computer modelling application with a set of structure coordinates of a molecule or molecular complex, at least a portion of the structural coordinates of the molecule or molecular complex being derived from, or defining the same relative spatial configuration as, at least a portion of the atomic coordinates Ser30, Tyr 31, Asp 49, Tφ90, and Ser91 of the light chain and Thr33, Tyr50, Asn52, Arg55, Tyr57, Lys74, Tyr99, AsplOl and Tyrl04 of the heavy chain of the OKT3 as set out in figure 5; (b) computationaUy building a model of an agent represented by a set of structure coordinates; and

(c) determining the level of structural similarity of the agent with the molecule or molecular complex, wherein a high level of structural similarity is indicative of potential binding to the CD3εγ. Of course the interaction of the complex with the TcR can also be blocked by designing drugs that preferentially interact with the complex and thus stop it forming a complex with the receptor. The present invention allows for the design of such molecules. In an even further aspect the present invention provides a computer or a software component thereof for producing a three-dimensional representation of a molecule or molecular complex, which includes a three-dimensional representation of a homologue of the molecule or molecular complex, in which the homologue includes a domain that has a root mean square deviation from the backbone atoms of the amino acids of not more than 2.1 A, in which the computer includes: (a) a machine-readable data storage medium including a data storage material encoded with machine-readable data, wherein the data includes the atomic coordinates of a binding domain of CD3εγ as set out in figure 5, (b) a working memory for storing instructions for processing the machine-readable data; (c) a central-processing unit coupled to the working memory and to the machine- readable data storage medium for processing the machine-readable data into the three-dimensional representation ; and

(d) a display coupled to the central-processing unit for displaying the three- dimensional representation. The binding domain used are the preferred binding domains of the invention as discussed previously. In one class of embodiments, the three-dimensional representation is of a molecule or molecular complex defined by the set of structure coordinates set out in Figures 5, or wherein the three-dimensional representation is of a homologue of the molecule or molecular complex, the homologue having a root mean square deviation from the backbone atoms of the amino acids of not more than 2.lA . hi a further aspect the invention provides an agent able to act as a ligand of CD3εγ. In a preferred embodiment the agent has been identified by a method described herein. In a preferred form of the invention the agent has a conformation and/or polarity such that it is capable of interacting with at least one amino acid residue selected from the group consisting of: Thr 12, Pro 13, Lys 15, Ser 17, Ser 19, Gly 20, Thr 21, Thr 22, He 24, Thr 26, Gln 29, Pro 31, Ser 33, Glu 34, Asn 40, Asp 41, Lys 42, Asn 43, Asp 47, Glu 48, Asp 49, Asp 50, Lys 51, Asn 52, Asp 56, Glu 57, Asp 58, His 59, Ser 61, Lys 63, Glu 64, Ser 66, Glu 67, Leu 68, Glu 69, Arg 79, Lys δ2, Pro δ3, Glu δ4, Asp δ5, Asn δ7, Arg 95 of the epsilon chain of CD3εγ. In another preferred embodiment the agent has a conformation and/or polarity such that it is capable of interacting with one or more amino acid residues selected from the group consisting of amino acids Glu 4δ, Asp 49, Asp 56, Glu 57, Asp 5δ, Glu 64, Glu 69 of the epsilon chain of the CD3εγ. In another preferred embodiment the agent has a conformation and/or polarity such that it is capable of interacting with one or more amino acid residues selected from the group consisting of amino acids Glu34, Gly46, Glu4δ, Arg79, GlyδO, Serδl, Lysδ2, Proδ3, Asp δ5 of the epsilon chain of CD3εγ. In a more preferred embodiment the agent interacts with a plurality of these amino acid residues, preferably all these amino acid residues. In another preferred embodiment the agent has a conformation and/or polarity such that it interacts with one or more of the atoms of the CD3ε chain identified in table 1 as being involved in binding of the CD3εγ to OKT3. In another preferred embodiment the agent has a conformation and or polarity such that it is capable of interacting with one or more amino acid residues selected from the group consisting Gln 1, Ser 2, Lys 4, Asn 6, Tyr 12, Asp 13, Ala 14, Glu 16, Asp 17, Thr 23, Asp 25, Glu 27, Ala 2δ, Lys 29, Asp 36, Lys 3δ, Thr 44, Glu 45, Asp 46, Lys 47, Lys 4δ, Lys 49, Asn 51, Ser 54, Ala 56, Lys 57, Asp 5δ, Arg 60, Lys 66, Ser 6δ, Gln 69, Asn 70, Lys 71, Lys 73, Arg δO of the gamma chain of CD3εγ. In another preferred embodiment the agent has a conformation and/or polarity such that it interacts with one or more amino acid residues selected from the group consisting of Lys 35, Lys 3 , Lys 57, Arg 60, Lys 66, Lys 71, Lys 73 of the gamma chain of the CD3εγ. Preferably the agent is capable of interacting with at least two amino acid residues, more preferably with at least three amino acid residues. Even more preferably agent is capable of interacting with at least four, still more preferably at least five amino acid residues, most preferably at least all these amino acid residues. In a particularly preferred embodiment the agent can interact with these residues when they adopt the conformation of the corresponding amino acids in figure 5. It is preferred that the agent has a high affinity for the selected target site. For in silico screening using computer modelling systems, the affinity constant is preferably <1 μM, more preferably < lnM. It will be clearly understood that pharmaceutically acceptable salts, derivatives and esters of the agents of the invention are also within the scope of the invention The agents entities of the invention may be formulated into pharmaceutical compositions, and administered in therapeutically effective doses. By "therapeutically effective dose" is meant a dose which results in at least partial alleviation of the symptoms or pathophysiological effects of the disease. The appropriate dose will be ascertainable by one skilled in the art using known techniques. Accordingly, a further aspect of the invention provides a composition comprising an agent according to the invention, together with a pharmaceutically-acceptable carrier. It will be appreciated that the composition may comprise two or more agents according to the invention. The agents and/or pharmaceutical compositions may be administered in a number of ways, including, but not limited to, orally, parentally, by inhalation spray, topically, rectally, nasally or via an implanted reservoir. Oral administration or administration by injection is preferred. The term parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intralesional, and intracranial injection or infusion techniques. The dosage to be used will depend on the nature and severity of the condition to be treated, and will be at the discretion of the attending physician or veterinarian. The most suitable dosage for a specific condition can be determined using normal clinical trial procedures. While it is particularly contemplated that the chemical entities of the invention are suitable for use in medical treatment of humans, they are also applicable to veterinary treatment, including treatment of companion animals such as dogs and cats, and domestic animals such as horses, cattle and sheep, or zoo animals such as felids, canids, bovids, and ungulates. Methods and pharmaceutical carriers for preparation of pharmaceutical compositions are well known in the art, as set out in textbooks such as Remington's Pharmaceutical Sciences, 19th Edition, Mack Publishing Company, Easton, Pennsylvania, USA. The agents and compositions of the invention may be administered by any suitable route, and the person skilled in the art will readily be able to determine the most suitable route and dose for the condition to be treated. Dosage will be at the discretion of the attendant physician or veterinarian, and will depend on the nature and state of the condition to be treated, the age and general state of health of the subject to be treated, the route of administration, and any previous treatment which may have been administered. Dosage levels of between about 0.01 and about 100 mg/kg body weight per day, preferably between about 0.5 and about 75 mg/kg body weight per day of the inhibitory compounds described herein are useful for the prevention and treatment transplant rejection. Typically, the pharmaceutical compositions of this invention will be administered from about 1 to about 5 times per day or alternatively, as a continuous infusion. Such administration can be used as a chronic or acute therapy. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. A typical preparation will contain from about 5% to about 95% active compound (w/w). Preferably, such preparations contain from about 20% to about δ0% active compound. The carrier or diluent, and other excipients, will depend on the route of administration, and again the person skilled in the art will readily be able to determine the most suitable formulation for each particular case. The term "pharmaceutically acceptable carrier" refers to a carrier(s) that is "acceptable" in the sense of being compatible with the other ingredients of a composition and not deleterious to the recipient thereof. Optionally, the pH of the formulation is adjusted with pharmaceutically acceptable acids, bases, or buffers to enhance the stability of the formulated compound or its delivery form. The present invention also encompases the treatment of conditions that are mediated by control of CD3εγ receptor signalling, hi one aspect therefore the present invention relates to the prophylaxis or treatment of a condition in which CD3εγ receptor signalling is implicated including administration of a therapeutically effective amount of an agent of the invention. There are a number of conditions in which this receptor signalling is implicated. The present invention also encompasses the use of agents that bind to the binding domains in the prevention of transplant rejection and or autoimmune conditions. In another aspect, there is provided a method of prophylaxis of transplant rejection the method including administering an effective amount of an agent of the present invention... In a particularly preferred embodiment the agent is able to bind to the binding domain when the domain is in the conformation defined by the relevant structural coordinates listed in figures 5 Preferably the agents are used to prevent transplant rejection in relation to kidney, heart, liver, skin and other transplants. It will be apparent to the skilled person that the compositions could be used for the prevention of transplant rejection for other parts of the body not expressly defined herein. In essence the agents and compositions of the invention could be used in preventing rej ection of any transplant. hi a further aspect there is provided a method of prophylaxis or treatment of an autoimmune condition including administration of an effective amount of an agent of the present invention. The autoimmune condition is selected from the group consisting of Multiple sclerosis, Myasthenia gravis, Guillain-Barre, Autoimmune uveitis, Crohn's Disease, Ulcerative colitis, Primary Bilary cirrhosis, Autoimmune hepatitis Autoimmune hemolytic anemia, Pernicious anemia, Autoimmune thrombocytopenia, immune mediated diabetes mellitus, Grave's Disease, Hashimoto's thyroiditis, Autoimmune oophoritis and orchitis, Autoimmune disease of the adrenal gland, Temporal arteritis, Anti-phospholipid syndrome, Vasculitides such as Wegener's granulomatosis, Behcet's disease, Rheumatoid arthritis, Systemic lupus erythematosus, Psoriasis, Scleroderma, Dermatitis heφetiformis, Polymyositis, dermatomyositis, Pemphigus vulgaris, Spondyloarthropathies such as ankylosing spondylitis, Sjogren's syndrome and Vitiligo. The present invention will now be more fully described with reference to the following examples. It should be understood, however, that the description following is illustrative only and should not be taken in any way as a restriction on the generality of the invention described above.

EXAMPLES EXAMPLE l DNA Isolation and Construction of Expression Plasmids for CD3 CD3gamma and CD3eρsilon were cloned from the human Eppstein-Barr virus-specific, HLA-Bδ-restricted T cell clone CF34 (Burrows ref.). RNA was reverse-transcribed with reverse transcriptase, using oligo-dT to prime, and cDNA was PCR-amplified with the following primers: 5'-CGCCATATGGATGGTAATGAAGAAATG-3' (SEQ ID NO:5) and 5'-CCCAAGCTTTTACACGCGTGCACGCAGGTAGAGATAAAAGTT-3' (SEQ ID NO:6) (epsilon) or 5'-CGCCATATGCAGTCAATCAAAGGAAAC-3' (SEQ ID NO:7) and 5'-CCCAAGCTTTTACATGCGGTAATACACTTGGAGTGG-3' (SEQ ID NO:8) (gamma), and T-A-cloned into the plasmid vector P-GEM T Easy (Promega). The cloned gene segments were verified by sequencing, and were predicted to each encode the single extracellular immunoglobulin-like domains, terminating immediately prior to the first of the cysteines in the stalk connecting the extracellular and transmembrane domains (Sun et aLCell, Vol. 105, 913-923, 2001):

DGNEEMGGIT QTPYKVSISG TTVILTCPQY PGSEJXWQHN DKNIGGDEDD KNIGSDEDHL SLKEFSELEQ SGYYVCYPRG SKPEDANFYL YLRARV (SEQ ID NO:9) (epsilon), and:

QSIKGNHLVK VYDYQEDGSV LLTCDAEAK ITWFKDGKMI GFLTEDKKKW NLGSNAKDPR GMYQCKGSQN KSKPLQVYYR M (SEQ ID NO:10) (gamma). A single-chain construct predicted to encode each of the above gamma and epsilon protein sequences, linked with the 26-residue peptide: GS ADDAKKDAAK KDDAKKDDAK KDGS (SEQ ID NO:ll) from the carboxy-terminus of gamma to the amino-terminus of epsilon was then engineered thus: the cloned gamma gene was PCR-amplified with the 2 primers: 5'-

CGCCATATGCAGTCAATCAAAGGAAAC-3' (Forward) (SEQ ID NO:12) and 5'- CTTTCTTTGCATCGTCCTTTTTGGCTGCGTCCTTCTTAGCGTCGTCAGCGCTGCC CATGCGGTAATACACTTG-3 ' (Reverse) (SEQ ID NO:13); and the cloned epsilon gene was similarly PCR-amplified with the 2 primers: 5'-

GACGCAGCCAAAAAGGACGATGCAAAGAAAGACGATGCGAAGAAGGACGGC AGCGATGGTAATGAAGAAATG-3' (Forward) (SEQ ID NO:14) and 5'- CCCAAGCTTTTACACGCGTGCACGCAGGTAGAGATAAAAGTT-3 ' (Reverse) (SEQ ID NO:15). The two PCR-derived gene fragments thus obtained, with 31 base-pairs complementarity, were then used as templates with the 2 primers: 5'- CGCCATATGCAGTCAATCAAAGGAAAC-3' (SEQ ID NO:16) and 5'- CCCAAGCTTTTACACGCGTGCACGCAGGTAGAGATAAAAGTT-3' (SEQ ID NO: 17) in a polymerase chain reaction, yielding a chimeric gene predicted to encode a protein with a 'gamma-linker-epsilon' structure. This gene was cloned as a Ndel-HindlH fragment into the pET-30 expression vector (Kjer-Nielsen).

Example 2 Expression and Purification of the Protein

Inclusion body protein of scCD3gamma-epsilon was prepared essentially as per the method of Garboczi et al. (Garboczi et al., 1996). The recombinant expression plasmid were transformed into BL21 (DE3) E. coli. A positive transformant was selected and grown at 37(C for 16 hours in LB plus kanamycin (30ug/ml) and chloramphenicol (34ug/ml). The inoculate was diluted 1/100 into a litre of LB medium containing antibiotics and grown to an OD600 of 0.6. The culture was induced with 1 mM IPTG and grown for a further 4 hours. Bacteria were pelleted, resuspended in 5 ml of resuspension buffer containing 50 mM Tris pH 8.0, 25% (w/v) sucrose, 1 mM EDTA, 10 mM DTT, 0.2 mM PMSF and 1 g/ml pepstatin, and then frozen at -70°C. The bacterial pellet was thawed, then lysed by the addition of 22.5 ml of lysis buffer containing 50 mM Tris pH 8.0, 1% (v/v) Triton X-100, 1% (w/v) sodium deoxycholate, 100 mM NaCl, 10 mM DTT, lmg Dnasel, 5 mM MgC12. After 20 minutes of continuous rocking at room temperature the samples were homogenised for 30 seconds using a Polytron homogenizer, after which lOmM EDTA was added. Inclusion bodies were isolated by centrifugation at 4°C, 10,000 φm for 15 minutes in a Sorvall GSA rotor. The pellets were resuspended in 150 ml of wash buffer containing 50 mM Tris pH 8.0, 0.5% (v/v) Triton X-100, 100 mM NaCl, 1 mM EDTA, 1 mM DTT, 0.2 mM PMSF and lug/ml pepstatin, homogenised and centrifuged. This wash step was repeated twice. A final wash in a buffer containing 50 mM Tris pH δ.0, 1 mM EDTA, 1 mM DTT, 0.2 mM PMSF and 1 ug/ml pepstatin was then performed. The inclusion bodies were resuspended in 20 mM Tris pH δ.0, δ M urea, 0.5 mM EDTA, 1 mM DTT, homogenised, and centrifuged at 4°C, 15,000 φm, for 30 minutes in an SS34 rotor. Inclusion body protein present in the supernatant was quantified by comparison of Coomassie blue-stained SDS-PAGE-fractionated aliquots and protein standards, before freezing at 70°C. XXmg of scCD3gamma-epsilon inclusion body protein was thawed, pulsed with 2umol/ml DTT, and injected into 400ml of stirring refolding buffer containing 200 mM Tris pH 8.5, 0.8M arginine, ImM oxidised glutathione, 0.2 mM reduced glutathione, 0.2 mM PMSF, 1 ug/ml PepstatinA at 4°C. 24 hr later refolded protein was dialysed (Spectrum; molecular weight cutoff 6-δ,000 kD) against three changes of 10 1 PBS. Dialysed protein was captured on a Protein A Sepharose Fast Flow column (Pharmacia) containing 50 mg of immobilized Mab OKT3 (Ref). Bound scCD3gamma-epsilon was eluted with 50 mM citrate, 20 mM Tris-HCl (pH 3.0) and 0.1 M NaCl,and peak fractions were immediately adjusted to pH 7.2-7.5 using 1 M Tris-HCl (pH 8.5), pooled, buffer-exchanged to 10 mM Tris (pH 8) and 150mM NaCl, concentrated to 2 ml and loaded onto a HiLoad 16/60 Superdex 75 pg gel filtration column (Amersham Pharmacia, Uppsala,Sweden) in the presence of 10 mM Tris.HCl (pH 8) and 150 mM NaCl. Fractions containing scCD3gamma-epsilon were pooled and concentrated to 5-10mg/ml, and analysed by SDS- PAGE. Example 3 Production of the CD3εγ/OKT3 complex

Supernatant containing OKT3 Mab was harvested from cells grown in Xten Hybricell serum free medium (# 11-410-0500V; ThermoTrace), in miniPerm production modules (# rV-76001055; Vivascience). OKT3 Mab was purified from supernatant by binding to a Protein A Sepharose 4 Fast Flow column (# 17-0974-02; Amersham Pharmacia), and was then eluted with 0.1M glycine pH 3, and neutralized with Tris.HCl to pH δ. For long-term storage purified OKT3 Mab was dialyzed against PBS, and sodium azide was added to a final concentration of 0.02%. To generate Fab fragments, purified OKT3 MAb was buffer-exchanged into 20 mM sodium phosphate, 10 mM EDTA buffer, pH 7, and concentrated to 20 mg/ml. 0.5 ml of digestion buffer containing 20 mM sodium phosphate, 10 mM EDTA and 20 mM cysteine.HCl, pH 7 was added to 0.5 ml of OKT3 Mab, and to this 0.5 ml of 50% immobilized papain agarose gel slurry in digestion buffer (# 20341; Pierce) was then added. The digest was incubated with constant mixing for five hours at 37°C. 1.5 ml of 10 mM Tris.HCl, pH 7.5 was then added to the digest, and the immobilized enzyme was removed by centrifugation.

To purify Fab from Fc fragments, the digest was passed over a Protein A Sepharose 4 Fast Flow column, and the flow-through containing Fab fragments was concentrated and buffer- exchanged to 10 mM Tris.HCl, pH δ. Fab fragments were then further purified by anion exchange chromatography on a Mono Q HR 10/10 column (Amersham Pharmacia), and by gel filtration on a HiLoad 16/60 Superdex 75 column (Amersham Pharmacia). Purified OKT3-Fab was thus obtained.

To generate scCD3ε-γ complexed to OKT3-Fab, a 2.6x molar excess of purified scCD3ε-γ was incubated for 16 hr with OKT3-Fab, in 10 mM Tris.HCl and 150 mM NaCl, pH 8. This mixture was then passed over a 16/60 Superdex 75 column, and scCD3ε-γ complexed to OKT3-Fab was resolved from excess free scCD3ε-γ. Complexes containing scCD3ε-γ bound to OKT3-Fab were concentrated and used for crystallization trials.

Example 4 Formation of the Crystals and Structure Elucidation

Small, rod-shaped crystals were grown using the hanging drop vapour diffusion technique at room temperature. The crystals were grown by mixing equal volumes of lOmg/ml CD3γε/OKT3 complex with the reservoir buffer (20% PEG 3350, 200mM potassium fluoride, pH 8). The crystals belong to space group P2 with unit cell dimensions a= 67.7, b = 55.5, c = 96.05 angstroms. In this preferred embodiment, the crystal preferably has angles α=90°, β=100.85°, γ=90°. The crystals were flash frozen prior to data collection using 15% glycerol as the cryoprotectant. The data were processed and scaled using the HKL package (Ottwinowski, 1993). For a summary of statistics see Table 3.

The structure was solved by the molecular replacement method, using programs from CCP4 Suite (CCP4, 1994). A human IgG Fab fragment (PDB code: IFOR) was used as the search probe. Unbiased features in the initial electron density maps in the vicinity of the hypervariable loops, coupled within sufficient space to pack a CD3 heterodimer suggested that the asymmetric unit contained a Fab OKT3/ CD3εγ complex. Attempts to use the NMR murine CD3εγ structure as a search probe failed to yield a correct solution. Nevertheless, sufficient phasing was provided from the Fab fragment to allow model building of the CD3 heterodimer to proceed. The progress of refinement was monitored by the Rfree value (4% of the data) with neither a sigma, nor a low resolution cut off being applied to the data. The structure was refined using rigid-body fitting followed by the simulated-annealing protocol implemented in CNS (version 1.0) (Brunger AT, 199δ), interspersed with rounds of model building using the program 'O'(Jones et al., 1991). Water molecules were included in the model using standard criteria. The final model, comprising residues 1-219 of the heavy chain, 1-213 of the light chain, residues 11-96 of CD3ε and 1-81 of CD3γ and 604 water molecules has an Rf_acto_r of 21.1% and an Rf_ree of 25.5% for all reflections between 50 and 2.1 A. See Table 1 for summary of refinement statistics and model quality. Two residues, Asp46 (CD3γ) and Thr50 (Light chain), lie within disallowed regions of the Ramachandran plot (Laskowski et al., 1993). Asp 46 lies within a poorly resolved loop (the C'-E loop, residues 45-49) of CD3γ; Thr50 lies within excellent electron density, and the corresponding residue in the search probe also lies within the disallowed region of the Ramachandran plot. The linker that covalently connects the CD3 heterodimer was not observed, and is presumably disordered. For structural comparisons, coordinates relating to the 12^th molecule in the NMR ensemble was considered to be the most representative CD3εγ structure (PDB code 1 JBJ). Table 3

Data collection statistics

Temperature 100 K

X-ray source RU3-HBR

Detector R-Axis IV^

Space Group P2ι

Cell dimensions(A) (a,b,c, 61.10, 5f 96.05, β) 100.δ5

Resolution (A) 2.1

Total N^0' observations 111297

N°^* unique observations 41156

Multiplicity 2.7

Data completeness (%) 99.4 (100)

No. data > 2στ δθ.5 (61.4)

JJσ_ϊ 12.9 (3.4)

Rmerge (%) 9.3 (43.δ)

Refinement statistics

Non hydrogen atoms Protein 4652 Water 604

Resolution (A) 50 - 2.1

Rfactor (%) 21.1

Rfree ³ (%) 25.5

Rms deviations from ideality Bond lengths (A) 0.005 Bond angles (°) 1.31 hnpropers (°) 0.76

Dihedrals (°) 26.74

Ramachandran plot Most favoured δδ.2 And allowed region (%) 10.4

B-factors (A²) Average main chain 23.9

Average side chain 24.9

Average water molecule 32.9 r.m.s. deviation bonded Bs 1.9

REFERENCES

Bartlett, P.A. CAVEAT: A Program to Facilitate the Structure-Derived Design of

Biologically Active Molecules. In Molecular Recognition in Chemical and Biological

Problems. Special Pub., Royal Chem. Soc, 78 pρ.182-196 (19δ9). Beddell, Drug development based on information regarding receptor structure. Chem. Soc.

Reviews 1985, 279.

Blundell et al., Nature 1987 326347.

Bohm H.-J., The Computer Program LUDI: A New Method for the De Novo Design of

Enzyme Inhibitors. J. Comp. Aid. Molec. Design 6, pp.61-7δ (1992) Brunger AT, Adams PD, Clore GM, DeLano WL, Gros P, Grosse-Kunstleve RW, Jiang

JS, Kuszewski J, Nilges M, Pannu NS, Read RJ, Rice LM, Simonson T, Warren GL.

(199δ) Acta Cryst D Biol Crystallogr 54 ( Pt 5):905-21

Cohen, N.C. et al. Molecular Modeling Software and Methods for Medicinal Chemistry, J.

Med. Chem., 33, pp.883-894 (1990). DeWitte, R.S., Shakhnovich, E.I. SMoG: de novo design method based on simple fast and accurate free energy estimates. 1. Methodology and supporting evidence. J. Am. Chem.

Soc. 11 δ: 11733-11744, 1996.

De Witte, R.S., Ischenko, A.V., Shakhnovich, E.I. SMoG. de novo design method based on simple fast and accurate free energy estimates. 2. Case studies in molecular design. J. Am. Chem. Soc. 119:4608-4617, 1997.

Eldridge, M.D., Murray, C.W., Auton, T.R., Paolini, G.V., Mee, R.P. Empirical scorint functions:I. The development of a fast empirical scoring function to estimate the binding affinity of ligands in receptor complexes. J. Comp.-Aided Mol. Des. 11 : 425-445, 1997.

Goodford, J. Med. Chem. 198427 557; Goodford, P.J. A Computational Procedure for Determining Energetically Favorable

Binding Sites on Biologically Important Macromolecules. J. Med. Chem., 28, pp.δ49-δ57

(1985).

Garboczi, D.N. et al. Assembly, specific binding and crystallisation of a human TCR aphabeta with an antigenic Tax peptide from Human T lymphotropic virustype 1 and the class i MHC molecule HLA-A2. J Immunol, 157, 5403-10.

Goodsell, D.S. et al. Automated Docking of Substrates to Proteins by Simulated

Annealing. Proteins: Structure, Function, and Genetics, 8, pp.195-202 (1990)

Hoi, Angew. Chem. 1986 25 767

Jones, T.A., Zou, J.-Y., Cowan, S.W. & Kjeldgaard, M. (1991) Acta Cryst. A47, 110-119 Kuntz, LD. et al. A Geometric Approach to Macromolecule-Ligand Interactions. J. Mol.

Biol. 161, pp.269-288 (19δ2)

Kuntz, I.D. Structure-based strategies for drug design and discovery. Science 257: 1078-

1082, 1992. Martin Y.C., 3D Database Searching in Drug Design. J. Med. Chem., 35, pp.2145-2154

(1992)

Meng, E.G. et al. J. Comp. Chem., 13, pp.505-524 (1992)

Miranker A. et al. Functionality Maps of Binding Sites: A Multiple Copy Simultaneous

Search Method. Proteins: Structure, Function and Genetics, 11, pp.29-34 (1991) Navia, M.A. et al. The Use of Structural Information in Drug Design, Current Opinions in

Structural Biology, 2, pρ.202-210 (1992)

Nishibata Y. et al., Tetrahedron, 47, ρ.89δ5 (1991)

Otwinowski, Z. (1993) (Sawyer, L., Issacs, N. & Bailey, S., eds) pp 55-62, SERC

Daresbury Laboratory, Warrington, UK. Tao, P. Lai, L. Protein ligand docking based on empirical method for binding affinity estimiation. J. Comp.-Aided Mol. Des. 15:429-446, 2001.

Verlinde C.L.M.J & Hoi, W.G.J. Structure 1994, 2, 577.

Wang, R., Lui, L., Lai, L., Tang, Y. SCORE: A new empirical method for estimating the binding affinity of a protein-ligand complex, j. Mol. Model. 4: 379-394, 199δ. Wang, R., Wang, S. How does consensus scoring work for virtual library screening? An idealized computer experiment. J. Chem. Inf. Comput. Sci. 2001..

M. M. Davis, P. J. Bjorkman, Nature 334, 395-402. (1988).

P. A. van der Merwe, S. j. Davis, Annu Rev Immunol 21, 659-84 (2003). D. N. Garboczi, W. E. Biddison, Immunity 10, 1-7. (1999). j. Hennecke, D. C. Wiley, Cell 104, 1-4. (2001).

K. C. Garcia, L. Teyton, I. A. Wilson, Annu Rev Immunol 17, 369-97 (1999).

M. E. Call, j. Pyrdol, M. Wiedmann, K. W. Wucheφfennig, Cell 111, 967-79 (Dec 27,

2002). B. Alarcon, D. Gil, P. Delgado, W. W. Schamel, Immunol Rev 191, 3δ-46 (Feb, 2003).

B. Malissen, Immunol Rev 191, 7-27 (Feb, 2003).

B. Berkhout, B. Alarcon, C. Terhorst, JBiol Chem 263, δ52δ-36 (Jun 15, 1988).

D. J. Kappes, B. Alarcon, J. R. Regueiro, Curr Opin Immunol 7, 441-7 (Aug, 1995).

J. B. DeJamette et α/., Proc Nat/ ,4cαd Set USA 95, 14909-14 (Dec 8, 1998). P. Perez-Aciego et al, JExp Med 174, 319-26 (Aug 1, 1991). V. P. Dave et al, Embo J\6, 1360-70 (Mar 17, 1997).

B. Wang et al, J Immunol 162, 8δ-94 (Jan 1, 1999).

C. Soudais, J. P. de ViUartay, F. Le Deist, A. Fischer, B. Lisowska-Grospierre, Nat Genet 3, 77-81 (Jan, 1993).

A. Borroto, A. Mallabiabarrena, J. P. Albar, A. C. Martinez, B. Alarcon, JBiol Chem 273, 12807-16 (May 22, 199δ).

Z. J. Sun, K. S. Kim, G. Wagner, E. L. Reinherz, Cell 105, 913-23 (Jun 29, 2001). N. Manolios, O. Kemp, Z. G. Li, Eur J Immunol 24, 84-92 (Jan, 1994). N. Manolios, Z. G. Li, Immunol Cell Biol 73, 532-6 (Dec, 1995). H. Saito et al, Proc Natl Acad Sci USA 84, 9131-4 (Dec, 19δ7). T. W. Gobel, J. P. Dangy, J Immunol 164, δ79-δ3 (Jan 15, 2000).

B. Alarcon et al, Embo JIQ, 903-12 (Apr, 1991).

A. Bernot, C. Auffray, Proc Natl Acad Sci USA 88, 2550-4 (Mar 15, 1991). M. P. Lefranc, Nucleic Acids Res 29, 207-9. (2001).

D. Gil, D. Gutierrez, B. Alarcon, JBiol Chem 276, 11174-9 (Apr 6, 2001).

D. Gil, W. W. Schamel, M. Montoya, F. Sanchez-Madrid, B. Alarcon, Cell 109, 901-12

(Jun 2δ, 2002).

L. Kjer-Nielsen et al, Immunity 18, 53-64 (Jan, 2003). S. J. Davis, P. A. van der Merwe, Curr Biol 11, R2δ9-91 (Apr 17, 2001).

S. J. Davis et al, Nat Immunol 4, 217-24 (Mar, 2003).

S. K. Bromley et al, Annu Rev Immunol 19, 375-96 (2001).

M. P. Macris, O. H. Frazier, D. Lammermeier, B. Radovancevic, J. M. Duncan, J Heart

Transplant 8, 2δ 1 -7 (Jul- Aug, 19δ9). T. H. Waid et al. , Transplant Proc 23, 1062-5 (Feb, 1991).

M. S. Kumar et al, Transplant Proc 30, 1351-2 (Jun, 199δ).

J. B. Matthews, E. Ramos, J. A. Bluestone, Am J Transplant 3, 794-803 (Jul, 2003).

C. Emmons, L. G. Hunsicker, Iowa Med 77, 78-82 (Feb, 1987).

C. Sgro, Toxicology 105, 23-9 (Dec 20, 1995). S. L. Smith, JTranspl Coord 6, 109-19; quiz 120-1 (Sep, 1996).

S. Panzer, R. L. Geller, F. H. Bach, Scand J Immunol 32, 359-71 (Oct, 1990).

D. Kabelitz, O. Janssen, C. Bracker, J Immunol Methods 107, 211-6 (Mar 16, 1988).

D. Xu et al, Cell Immunol 200, 16-26 (Feb 25, 2000).

E. L. Masteller, J. A. Bluestone, Curr Opin Immunol 14, 652-9 (Oct, 2002). T. O. Utset et al, JRheumatol 29, 1907-13 (Sep, 2002).

J. A. Smith, J. Y. Tso, M. R. Clark, M. S. Cole, J. A. Bluestone, JExp Med 185, 1413-22

(Apr 21, 1997).

M. Belghith et al, Nat Med 9, 1202-8 (Sep, 2003).

K. S. Kim, Z. Y. Sun, G. Wagner, E. L. Reinherz, J Mol Biol 302, 899-916 (Sep 29, 2000).

J. Dietrich et al., J Cell Biol 132, 299-310 (Feb, 1996).

SEQUENCE LISTING

<110:> Monash University RossJohn, Jamie Beddoe, Travis Dunstone, Michelle Ely, Lauren McCluskey, James Kjer-Nielsen, Lars KoKostenko, Luda Purcell, Anthony

<120> Crystal Structure of CD3EY/0KT3 Complex

<130> 702657

<160> 17

<170> Patentln version 3.3

<210> 1

<211> 213

<212> PRT

<213> Mus musculus

<400> 1

Gln lie Val Leu Thr Gln Ser Pro Ala lie Met Ser Ala Ser Pro Gly 1 5 10 15

Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met 20 25 30

Asn Trp Tyr Gln Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp lie Tyr 35 40 45 Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ala His Phe Arg Gly Ser 50 55 60

Gly Ser Gly Thr Ser Tyr Ser Leu Thr lie Ser Gly Met Glu Ala Glu 65 70 75 80

Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Phe Thr 85 90 95

Phe Gly Ser Gly Thr Lys Leu Glu lie Asn Arg Ala Asp Thr Ala Pro 100 105 110

Thr Val Ser lie Phe Pro Pro Ser Ser Glu Gln Leu Thr Ser Gly Gly 115 120 125

Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr Pro Lys Asp lie Asn 130 135 140

Val Lys Trp Lys lie Asp Gly Ser Glu Arg Gln Asn Gly Val Leu Asn 145 150 155 160

Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr Tyr Ser Met Ser Ser 165 170 175

Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg His Asn Ser Tyr Thr 180 185 190

Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro lie Val Lys Ser Phe 195 200 205 Asn Arg Asn Glu Cys 210

<210> 2

<211> 219

<212> PRT

<213> Mus musculus

<400> 2

Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala 1 5 10 15

Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Tyr 20 25 30

Thr Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp lie 35 40 45

Gly Tyr lie Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn Gln Lys Phe 50 55 60

Lys Asp Lys Ala Thr Leu Thr Thr Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80

Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Thr Leu Thr Val Ser Ser Ala Lys Thr Thr Ala Pro Ser Val Tyr 115 120 125

Pro Leu Ala Pro Val Cys Gly Gly Thr Thr Gly Ser Ser Val Thr Leu 130 135 140

Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Leu Thr Trp 145 150 155 160

Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175

Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Thr Ser Ser 180 185 190

Thr Trp Pro Ser Gln Ser lie Thr Cys Asn Val Ala His Pro Ala Ser 195 200 205

Ser Thr Lys Val Asp Lys Lys lie Glu Pro Arg 210 215

<210> 3

<211> 86

<212> PRT

<213> Homo sapiens

<400> 3

Gln Thr Pro Tyr Lys Val Ser lie Ser Gly Thr Thr Val lie Leu Thr 1 5 10 15 Cys Pro Gln Gly Pro Gly Ser Glu lie Leu Trp Gln His Asn Asp Lys 20 25 30

Asn lie Gly Gly Asp Glu Asp Asp Lys Asn lie Gly Ser Asp Glu Asp 35 40 45

His Leu Ser Leu Lys Glu Phe Ser Glu Leu Glu Gln Ser Gly Tyr Tyr 50 55 60

Val Cys Tyr Pro Arg Gly Ser Lys Pro Glu Asp Ala Asn Phe Tyr Leu 65 70 75 80

Tyr Leu Arg Ala Arg Val 85

<210> 4

<211> 82

<212> PRT <213> Homo sapiens

<400> 4

Met Gln Ser lie Lys Gly Asn His Leu Val Lys Val Tyr Asp Ala Gln 1 5 10 15

Glu Asp Gly Ser Val Leu Leu Thr Cys Asp Ala Glu Ala Lys Asn lie 20 25 30

Thr Trp Phe Lys Asp Gly Lys Met lie Gly Phe Leu Thr Glu Asp Lys 35 40 45 Lys Lys Trp Asn Leu Gly Ser Asn Ala Lys Asp Pro Arg Gly Met Tyr 50 55 60

Gln Cys Lys Gly Ser Gln Asn Lys Ser Lys Pro Leu Gln Val Tyr Tyr 65 70 75 80

Arg Met

<210> 5 <211> 27

<212> DNA

<213> Homo sapiens

<400> 5 cgccatatgg atggtaatga agaaatg 27

<210> 6

<211> 42 <212> DNA

<213> Homo sapiens

<400> 6 cccaagcttt tacacgcgtg cacgcaggta gagataaaag tt 42

<210> 7

<211> 27

<212> DNA <213> Homo sapiens r

<400> 7 cgccatatgc agtcaatcaa aggaaac 27 <210> 8

<211> 36

<212> DNA <213> Homo sapiens

<400> 8 cccaagcttt tacatgcggt aatacacttg gagtgg 36

<210> 9

<211> 94

<212> PRT

<213> Homo sapiens

<400> 9

Asp Gly Asn Glu Glu Met Gly Gly He Thr Gln Thr Pro Tyr Lys Val 1 5 10 15

Ser He Ser Gly Thr Thr Val He Leu Thr Cys Pro Gln Tyr Pro Gly 20 25 30

Ser Glu He Leu Trp Gln His Asn Asp Lys Asn He Gly Gly Asp Glu 35 40 45

Asp Asp Lys Asn He Gly Ser Asp Glu Asp His Leu Ser Leu Lys Glu 50 55 60

Phe Ser Glu Leu Glu Gln Ser Gly Tyr Tyr Val Cys Tyr Pro Arg Gly 65 70 75 80

Ser Lys Pro Glu Asp Ala Asn Phe Tyr Leu Tyr Leu Arg Ala 85 90 <210> 10

<211> 81 <212> PRT

<213> Homo sapiens

<400> 10

Gln Ser He Lys Gly Asn His Leu Val Lys Val Tyr Asp Tyr Gln Glu 1 5 10 15

Asp Gly Ser Val Leu Leu Thr Cys Asp Ala Glu Ala Lys Asn He Thr 20 25 30

Trp Phe Lys Asp Gly Lys Met He Gly Phe Leu Thr Glu Asp Lys Lys 35 40 45

Lys Trp Asn Leu Gly Ser Asn Ala Lys Asp Pro Arg Gly Met Tyr Gln 50 55 60

Cys Lys Gly Ser Gln Asn Lys Ser Lys Pro Leu Gln Val Tyr Tyr Arg 65 70 ^• 75 80

Met

<210> 11 <211> 24

<212> PRT

<213> Homo sapiens

<400> 11 Ala Asp Asp Ala Lys Lys Asp Ala Ala Lys Lys Asp Asp Ala Lys Lys 1 5 10 15

Asp Asp Ala Lys Lys Asp Gly Ser 20

<210> 12

<211> 27

<212> DNA

<213> Homo sapiens

<400> 12 cgccatatgc agtcaatcaa aggaaac 27

<210> 13 <211> 73

<212> DNA

<213> Homo sapiens

<400> 13 ctttctttgc atcgtccttt ttggctgcgt ccttcttagc gtcgtcagcg ctgcccatgc 60

ggtaatacac ttg 73

<210> 14

<211> 72

<212> DNA

<213> Homo sapiens

<400> 14 gacgcagcca aaaaggacga tgcaaagaaa gacgatgcga agaaggacgg cagcgatggt 60

aatgaagaaa tg 72 <210> 15

<211> 42

<212> DNA <213> Homo sapiens

<400> 15 cccaagcttt tacacgcgtg cacgcaggta gagataaaag tt 42

<210> 16

<211> 27

<212> DNA

<213> Homo sapiens

<400> 16 cgccatatgc agtcaatcaa aggaaac 27

<210> 17

<211> 42

<212> DNA

<213> Homo sapiens

<400> 17 cccaagcttt tacacgcgtg cacgcaggta gagataaaag tt 42

Claims

CLAIMS:

1. A crystal of the extracellular domain of a CD3 receptor in complex with OKT3 monoclonal antibody or a derivative thereof.

2. A crystal according to claim 1 wherein the crystal is of the CD3εγ heterodimer in complex with OKT3 monoclonal antibody or a derivative thereof.

3. A crystal according to claim 1 or 2 wherein the crystal has the orthorhombic space group symmetry P21.

4. A crystal according to any one of claim 1 to 3 wherein the crystal has unit cell dimensions (a,b,c), wherein a is from about 45 angstroms to about δ5 angstroms, b is about 45 angstroms to about 65 angstroms and c is about δO angstroms to about 120 angstroms.

5. A crystal according to any one of the proceeding claims wherein the crystal has unit cell dimensions a= 67.7, b = 55.5, c = 96.05 angstroms.

6. A crystal according to any one of the proceeding claims wherein the crystal has angles α=90°, β=100.δ5°, γ=90°.

7. A crystal according to any one of the proceeding claims wherein the crystal has the orthorhombic space group symmetry P2₁2₁2₁.

δ. A crystal according to any one of the proceeding claims wherein the crystal has atoms arranged in the spatial relationship represented by the structure coordinates listed in figure 5.

9. A binding domain or portion thereof of the CD3εγ heterodimer.

10. A binding domain according to claim 9 wherein the binding domain includes at least one amino acid selected from the group consisting of: Thr 12, Pro 13, Lys 15, Ser 17, Ser 19, Gly 20, Thr 21, Thr 22, He 24, Thr 26, Gln 29, Pro 31, Ser 33, Glu 34, Asn 40, Asp 41, Lys 42, Asn 43, Asp 47, Glu 48, Asp 49, Asp 50, Lys 51, Asn 52, Asp 56, Glu 57, Asp 58, His 59, Ser 61, Lys 63, Glu 64, Ser 66, Glu 67, Leu 68, Glu 69, Arg 79, Lys 82, Pro 83, Glu 84, Asp 85, Asn 87, Arg 95 of the epsilon chain of the CD3εγ.

11. A binding domain according to claim 9 or 10 wherein the domain includes at least one amino acid selected from the group consisting of Glu 48, Asp 49, Asp 56, Glu 57, Asp

58, Glu 64, Glu 69 of the epsilon chain of the CD3εγ.

12. A binding domain according to any one of claims 9 to 11 wherein the domain includes at least one amino acid selected from the group consisting of: Gln 1, Ser 2, Lys 4, Asn 6, Tyr 12, Asp 13, Ala 14, Glu 16, Asp 17, Thr 23, Asp 25, Glu 27, Ala 28, Lys 29, Asp 36, Lys 38, Thr 44, Glu 45, Asp 46, Lys 47, Lys 48, Lys 49, Asn 51, Ser 54, Ala 56, Lys 57, Asp 58, Arg 60, Lys 66, Ser 68, Gln 69, Asn 70, Lys 71, Lys 73, Arg 80 of the gamma chain of the CD3εγ.

13. A binding domain according to any one of claims 9 to 12 wherein the domain includes at least one amino acid selected from the group consisting of Lys 35, Lys 3δ, Lys 57, Arg 60, Lys 66, Lys 71, Lys 73 of the gamma chain of the CD3εγ.

14. A binding domain according to any one of claims 9 to 13 wherein the domain includes at least one amino acid residue selected from the group consisting of Glu34,

Gly46, Glu4δ, Arg79, Gly80, Ser81, Lysδ2, Proδ3, Asp 85 of the epsilon chain of the CD3εγ.

15. A binding domain according to any one of claims 9 to 14 wherein the amino acid residues in each of the binding domains are in the same relative spatial configuration as the corresponding amino acid residues in figure 5.

16. A binding domain or portion thereof of the OKT3 monoclonal antibody that recognises the CD3 receptor.

17. A binding domain according to claim 16 wherein the binding domain includes at least one amino acid residue selected from the group consisting of: Ser30, Tyr 31, Asp 49, Tφ90, and Se 91 of the light chain and Thr33, Tyr50, Asn52, Arg55, Tyr57, Lys74, Tyr99, AsplOl and Tyr 104 of the heavy chain of the OKT3 or an equivalent amino acid residue.

18. A binding domain according to claim 16 or 17 wherein the amino acid residues in the binding domain are in the same relative spatial configuration as the corresponding amino acid residues in figure 5.

19. A molecule or molecular complex wherein at least a portion of the structural coordinates of the molecule or molecular complex define the same relative spatial configuration as at least a portion of the structural coordinates of the CD3εγ receptor as set out in figure 5.

20. A molecule or molecular complex according to claim 19 wherein at least a portion of the coordinates of the molecule or molecular complex define the same relative spatial configuration as at least a portion of the coordinates of the binding domain defined by amino acid residues Thr 12, Pro 13, Lys 15, Ser 17, Ser 19, Gly 20, Thr 21, Thr 22, He 24, Thr 26, Gln 29, Pro 31, Ser 33, Glu 34, Asn 40, Asp 41, Lys 42, Asn 43, Asp 47, Glu 48, Asp 49, Asp 50, Lys 51, Asn 52, Asp 56, Glu 57, Asp 58, His 59, Ser 61, Lys,63, Glu 64, Ser 66, Glu 67, Leu 68, Glu 69, Arg 79, Lys 82, Pro 83, Glu 84, Asp 85, Asn 87, Arg 95 of the epsilon chain of the CD3εγ.

21. A molecule or molecular complex according to claim 19 or 20 wherein at least a portion of the coordinates of the molecule or molecular complex define the same relative spatial configuration as at least a portion of the coordinates of a binding domain defined by amino acid residues Glu 48, Asp 49, Asp 56, Glu 57, Asp 58, Glu 64, Glu 69 of the epsilon chain of the CD3εγ.

22. A molecule or molecular complex according to claim 21 wherein the molecule or molecular complex has coordinates that define the same relative spatial configuration as the coordinates of a binding domain defined by amino acid residues Glu 48, Asp 49, Asp 56, Glu 57, Asp 58, Glu 64, Glu 69 of the epsilon chain of the CD3εγ.

23. A molecule or molecular complex according to any one of claims 19 to 22 wherein at least a portion of the coordinates of the molecule or molecular complex define the same relative spatial configuration as at least a portion of the coordinates of the binding domain defined by amino acid residues Gln 1, Ser 2, Lys 4, Asn 6, Tyr 12, Asp 13, Ala 14, Glu 16, Asp 17, Thr 23, Asp 25, Glu 27, Ala 28, Lys 29, Asp 36, Lys 38, Thr 44, Glu 45, Asp 46, Lys 47, Lys 48, Lys 49, Asn 51, Ser 54, Ala 56, Lys 57, Asp 58, Arg 60, Lys 66, Ser 68, Gln 69, Asn 70, Lys 71, Lys 73, Arg 80 of the gamma chain of CD3 of the CD3εγ.

24. A molecule or molecular complex according to any one of claims 19 to 23 wherein at least a portion of the coordinates of the compound or molecular complex define the same relative spatial configuration as at least a portion of the coordinates of a binding domain defined by amino acid residues Lys 35, Lys 38, Lys 57, Arg 60, Lys 66, Lys 71, Lys 73 of the gamma chain of the CD3εγ.

25. A molecule or molecular complex according to any one of claims 19 to 24 wherein the molecule or molecular complex has coordinates that define the same relative spatial configuration as a binding domain defined by amino acid residues Lys 35, Lys 38, Lys 57, Arg 60, Lys 66, Lys 71, Lys 73 of the gamma chain of the CD3εγ.

26. A molecule or molecular complex according to claim 19 wherein at least a portion of the structural coordinates of the molecule or molecular complex define the same relative spatial configuration as at least a portion of the coordinates of residues Glu 34, Gly 46, Glu 48, Arg 79, Gly 80, Ser 81, Lys 82, Pro 83, Asp 85 of the epsilon chain of the CD3εγ.

27. A molecule or molecular complex according to claim 26 wherein at least a portion of the structure coordinates of the molecule or molecular complex define the same relative spatial configuration as the coordinates of Glu34, Gly46, Glu4δ, Arg79, GlyδO, Serδl, Lys82, Pro83, Asp 85 of the epsilon chain of CD3εγ.

28. A molecule or molecular complex according to claim 19 wherein at least a portion of the structural coordinates of the molecule or molecular complex define the same relative spatial configuration as at least a portion of the structure coordinates of the atoms of the CD3ε chain identified in table 1 as being involved in binding of the CD3εγ to OKT3.

29. A molecule or molecular complex wherein at least a portion of the structural coordinates of the molecule or molecular complex define the same relative spatial configuration as at least a portion of the structure coordinates of the OKT3 in figure 5.

30. A molecule or molecular complex according to claim 29 wherein at least a portion of the structural coordinates of the molecule or molecular complex define the same relative spatial configuration as at least a portion of the coordinates of residues : Ser30, Tyr 31, Asp 49, Tφ90, and Ser91 of the light chain and Thr33, Tyr50, Asn52, Arg55, Tyr57, Lys74, Tyr99, AsplOl and Tyr 104 of the heavy chain of the OKT3 as set out in figure 5.

31. A molecule or molecular complex according to claim 30 wherein at least a portion of the structure coordinates of the molecule or molecular complex define the same relative spatial configuration as the coordinates of a plurality of residues selected from the group consisting of : Ser30, Tyr 31, Asp 49, Tφ90, and Ser91 of the light chain and Thr33, Tyr50, Asn52, Arg55, Tyr57, Lys74, Tyr99, AsplOl and Tyrl04 of the heavy chain of the OKT3 as set out in figure 5.

32. A molecule or molecular complex according to claim 30 wherein at least a portion of the structural coordinates of the molecule or molecular complex define the same relative spatial configuration as at least a portion of the structure coordinates of the atoms of the OKT3 light and heavy chain identified in table 1 as being involved in binding of the OKT3 to CD3εγ.

33. A data set defining a scalable three-dimensional configuration of points at least a portion of the data set being derived from, or defining the same relative spatial configuration as, at least a portion of the structure coordinates of a CD3/OKT3 complex.

34. A data set according to claim 33 wherein at least a portion of the data is derived from or defines the same relative spatial configuration as at least a portion of the structure coordinates of a crystalline CD3/OKT3 complex as set out in figure 5.

35. A data set according to claim 34 wherein at least a portion of the data in the data set is derived from or defines the same relative spatial configuration as at least a portion of the structural coordinates for amino acid residues Thr 12, Pro 13, Lys 15, Ser 17, Ser 19, Gly 20, Thr 21, Thr 22, He 24, Thr 26, Gln 29, Pro 31, Ser 33, Glu 34, Asn 40, Asp 41, Lys 42, Asn 43, Asp 47, Glu 48, Asp 49, Asp 50, Lys 51, Asn 52, Asp 56, Glu 57, Asp 58, His 59, Ser 61, Lys 63, Glu 64, Ser 66, Glu 67, Leu 68, Glu 69, Arg 79, Lys 82, Pro 83, Glu 84, Asp 85, Asn 87, Arg 95 of the epsilon chain of CD3εγ.

36. A data set according to claim 34 wherein at least a portion of the data in the data set is derived from or defines the same relative spatial configuration as at least a portion of the structural coordinates for amino acids Glu 48, Asp 49, Asp 56, Glu 57, Asp 5δ, Glu 64, Glu 69 of the epsilon chain of CD3εγ.

37. A data set according to claim 34 wherein at least a portion of the data in the data set is derived from or defines the same relative spatial configuration as at least a portion of the structural coordinates for amino acids Glu34, Gly46, Glu4δ, Arg79, GlyδO, Serδl, Lysδ2, Proδ3, Asp δ5 of the epsilon chain of CD3εγ.

38. A data set according to claim 34 wherein at least a portion of the data set is derived from or defines the same relative spatial configuration as at least a portion of the structure coordinates of the atoms of the CD3ε chain identified in table 1 as being involved in binding of the CD3εγ to OKT3.

39 A data set according to claim 34 wherein at least a portion of the data in the data set is derived from or defines the same relative spatial configuration as at least a portion of the structural coordinates for amino acid residues Gln 1, Ser 2, Lys 4, Asn 6, Tyr 12, Asp 13, Ala 14, Glu 16, Asp 17, Thr 23, Asp 25, Glu 27, Ala 28, Lys 29, Asp 36, Lys 38, Thr 44, Glu 45, Asp 46, Lys 47, Lys 48, Lys 49, Asn 51, Ser 54, Ala 56, Lys 57, Asp 58, Arg 60, Lys 66, Ser 68, Gln 69, Asn 70, Lys 71, Lys 73, Arg 80 of the gamma chain of the CD3εγ.

40. A data set according to claim 34 wherein at least a portion of the data in the data set is derived from or defines the same relative spatial configuration as at least a portion of the structural coordinates for amino acids residues Lys 35, Lys 38, Lys 57, Arg 60, Lys 66, Lys 71, Lys 73 of the gamma chain of the CD3εγ.

41. A data set according to claim 34 wherein at least a portion of the data in the data set is derived from or defines the same relative spatial configuration as at least a portion of the coordinates of Ser30, Tyr 31, Asp 49, Tφ90, and Ser91 of the light chain and Thr33, Tyr50, Asn52, Arg55, Tyr57, Lys74, Tyr99, AsplOl and Tyrl04 of the heavy chain of the OKT3 of the CD3εγ.

42. A data set according to claim 41 wherein the data set includes data derived from or defining the same relative spatial configuration as the coordinates of a plurality of these amino acid residues, preferably all of these amino acid residues.

43. A data set according to claim 41 wherein at least a portion of the structural coordinates of the data set are derived from or define the same relative spatial configuration as at least a portion of the structure coordinates of the atoms of the OKT3 light and heavy chain identified in table 1 as being involved in binding of the OKT3 to CD3εγ.

44. A scalable three dimensional configuration of points, at least a portion of the points being derived from, or defining the same relative spatial configuration as, at least a portion of the structure coordinates of a CD3/OKT3 complex.

45. A scalable three dimensional configuration of points according to claim 44 wherein at least a portion of points are derived from or defines the same relative spatial configuration as at least a portion of the structure coordinates of a crystalline CD3/OKT3 complex as set out in figure 5.

46. A scalable three dimensional configuration of points according to claim 45 wherein at least a portion of the points is derived from or defines the same relative spatial configuration as at least a portion of the structural coordinates of amino acid residues Thr 12, Pro 13, Lys 15, Ser 17, Ser 19, Gly 20, Thr 21, Thr 22, He 24, Thr 26, Gln 29, Pro 31, Ser 33, Glu 34, Asn 40, Asp 41, Lys 42, Asn 43, Asp 47, Glu 4δ, Asp 49, Asp 50, Lys 51, Asn 52, Asp 56, Glu 57, Asp 5δ, His 59, Ser 61, Lys 63, Glu 64, Ser 66, Glu 67, Leu 6δ, Glu 69, Arg 79, Lys δ2, Pro δ3, Glu δ4, Asp δ5, Asn δ7, Arg 95 of the epsilon chain of CD3εγ.

47. A scalable three dimensional configuration of points according to claim 45 wherein at least a portion of the points is derived from or defines the same relative spatial configuration as at least a portion of the structural coordinates for amino acids Glu 48, Asp 49, Asp 56, Glu 57, Asp 58, Glu 64, Glu 69 of the epsilon chain of the CD3εγ.

48. A scalable three dimensional configuration of points according to claim 45 wherein at least a portion of the points are derived from or defines the same relative spatial configuration as at least a portion of the structural coordinates for amino acids Glu34, Gly46, Glu48, Arg79, Gly80, Ser81, Lysδ2, Proδ3, Asp δ5 of the epsilon chain of the CD3εγ.

49. A scalable three dimensional configuration of points according to claim 45 wherein at least a portion of the points are derived from or define the same relative spatial configuration as at least a portion of the structure coordinates of the atoms of the CD3ε chain identified in table 1 as being involved in binding of the CD3εγ to OKT3.

50. A scalable three dimensional configuration of points according to claim 45 wherein at least a portion of the points are derived from or defines the same relative spatial configuration as at least a portion of the structural coordinates for amino acid residues Gln 1, Ser 2, Lys 4, Asn 6, Tyr 12, Asp 13, Ala 14, Glu 16, Asp 17, Thr 23, Asp 25, Glu 27, Ala 28, Lys 29, Asp 36, Lys 38, Thr 44, Glu 45, Asp 46, Lys 47, Lys 48, Lys 49, Asn 51, Ser 54, Ala 56, Lys 57, Asp 58, Arg 60, Lys 66, Ser 68, Gln 69, Asn 70, Lys 71, Lys 73, Arg 80 of the gamma chain of CD3εγ.

51. A scalable three dimensional configuration of points according to claim 45 wherein at least a portion of the points are derived from or defines the same relative spatial configuration as at least a portion of the structural coordinates for amino acids residues Lys 35, Lys 38, Lys 57, Arg 60, Lys 66, Lys 71, Lys 73 of the gamma chain of the CD3εγ.

52. A scalable three dimensional configuration of points according to claim 45 wherein at least a portion of the points is derived from or defines the same relative spatial configuration as the coordinates of Ser30, Tyr 31, Asp 49, Tφ90, and Ser91 of the light chain and Thr33, Tyr50, Asn52, Arg55, Tyr57, Lys74, Tyr99, AsplOl and Tyrl04 of the heavy chain of the OKT3.

53. A method of identifying an agent which is capable of acting as a ligand of CD3εγ the method including the step of identifying an agent that has a conformation and/or polarity such that it is capable of interacting with at least one relevant amino acid residue or portion thereof of the CD3εγ.

54. A method according to claim 53 wherein the method includes the step of identifying an agent that has a conformation and/or polarity such that it is capable of interacting with one or more amino acid residues selected from the group consisting of: Thr 12, Pro 13, Lys 15, Ser 17, Ser 19, Gly 20, Thr 21, Thr 22, He 24, Thr 26, Gln 29, Pro 31, Ser 33, Glu 34, Asn 40, Asp 41, Lys 42, Asn 43, Asp 47, Glu 48, Asp 49, Asp 50, Lys 51, Asn 52, Asp 56, Glu 57, Asp 58, His 59, Ser 61, Lys 63, Glu 64, Ser 66, Glu 67, Leu 68, Glu 69, Arg 79, Lys 82, Pro 83, Glu 84, Asp 85, Asn 87, Arg 95 of the epsilon chain of CD3εγ.

55. A method according to claim 53 wherein the method includes the step of identifying an agent that has a conformation and/or polarity such that it is capable of interacting with one or more amino acid residues selected from the group consisting of amino acids Glu 48, Asp 49, Asp 56, Glu 57, Asp 58, Glu 64, Glu 69 of the epsilon chain ofCD3εγ.

56. A method according to claim 53 wherein the method includes the step of identifying an agent that has a conformation and/or polarity such that it is capable of interacting with one or more amino acid residues selected from the group consisting of amino acids Glu34, Gly46, Glu48, Arg79, GlyδO, Serδl, Lysδ2, Proδ3, Asp δ5 of the epsilon chain of CD3εγ.

57. A method according to any one of claims 54 to 56 wherein the agent interacts with a plurality of these amino acid residues, preferably all these amino acid residues.

58. A method according to claim 53 wherein the method includes the step of identifying an agent that has a conformation and/or polarity such that it is capable of interacting with one or more of the atoms of the CD3ε chain identified in table 1 as being involved in binding of the CD3εγ to OKT3.

59. A method according to claim 53 wherein the method includes the step of identifying an agent that has a conformation and/or polarity such that it is capable of interacting with one or more amino acid residues selected from the group consisting Gln 1, Ser 2, Lys 4, Asn 6, Tyr 12, Asp 13, Ala 14, Glu 16, Asp 17, Thr 23, Asp 25, Glu 27, Ala 28, Lys 29, Asp 36, Lys 38, Thr 44, Glu 45, Asp 46, Lys 47, Lys 48, Lys 49, Asn 51, Ser 54, Ala 56, Lys 57, Asp 58, Arg 60, Lys 66, Ser 68, Gln 69, Asn 70, Lys 71, Lys 73, Arg 80 of the gamma chain of the CD3εγ.

60. A method according to claim 53 wherein the method includes the step of identifying an agent that has a conformation and/or polarity such that it is capable of interacting with one or more amino acid residues selected from the group consisting of Lys 35, Lys 38, Lys 57, Arg 60, Lys 66, Lys 71, Lys 73 of the gamma chain of the CD3εγ.

61. A method according to claim 53 wherein the method involves computer assisted modelling.

62. A method according to any one of claims 53 to 61 wherein the amino acid residues have the same relative spatial configuration as the corresponding amino acid residues as the structure coordinates of a crystalline CD3/OKT3 complex as set out in figure 5.

63. A computer-assisted method for identifying an agent capable of binding to the binding domain of a CD3εγ including the steps of:

(b) supplying the computer modelling application with a set of structure coordinates of an agent; and (c) determining whether the agent is expected to bind to the molecule or molecular complex, wherein binding to the molecule or molecular complex is indicative of binding to the CD3εγ.

64. A computer-assisted method for designing an agent capable of binding to the binding domain of a CD3εγ including the steps of:

(a) supplying a computer modelling application with a set of structure coordinates of a molecule or molecular complex, at least a portion of the structural coordinates of the molecule or molecular complex being derived from, or defining the same relative spatial configuration as, at least a portion of the atomic, coordinates of a CD3εγ binding domain as set out in figure 5

(b) supplying the computer modelling application with a set of structure coordinates for an agent; (c) evaluating the potential binding interactions between the agent and substrate binding pocket of the molecule or molecular complex;

(d) structurally modifying the agent to yield a set of structure coordinates for a modified agent; and

(e) determining whether the modified agent is expected to bind to the molecule or molecular complex, wherein binding to the molecule or molecular complex is indicative of a potential ligand of CD3εγ.

65. A method according to claim 63 or 64 wherein the step of supplying the computer with a set of structure coordinates of an agent involves provision of the coordinates from a chemical library of compounds.

66. A computer-assisted method for designing an agent capable of binding to a CD3εγ including:

(a) supplying a computer modelling application with a set of structure coordinates of a molecule or molecular complex, at least a portion of the structural coordinates of the molecule or molecular complex being derived from, or defining the same relative spatial configuration as, at least a portion of the atomic coordinates of the CD3εγ binding domain as .set out in figure 5;

(b) computationally building an agent represented by set of structure coordinates; and (c) determining whether the agent is expected to bind to the molecule or molecular complex, wherein binding to the molecule or molecular complex is indicative of potential binding to the CD3εγ.

67. A method according to any one of claims 63 to 66 wherein in step (a) at least a portion of the structure coordinates of the molecule or molecular complex define the same relative spatial configuration as at least a portion of the atomic coordinates corresponding to Thr 12, Pro 13, Lys 15, Ser 17, Ser 19, Gly 20, Thr 21, Thr 22, He 24, Thr 26, Gln 29, Pro 31, Ser 33, Glu 34, Asn 40, Asp 41, Lys 42, Asn 43, Asp 47, Glu 48, Asp 49, Asp 50, Lys 51, Asn 52, Asp 56, Glu 57, Asp 58, His 59, Ser 61, Lys 63, Glu 64, Ser 66, Glu 67, Leu 68, Glu 69, Arg 79, Lys 82, Pro 83, Glu 84, Asp 85, Asn 87, Arg 95 of the epsilon chain of CD3εγ as set out in figure 5.

68. A method according to any one of claims 63 to 66 wherein in step (a) at least a portion of the structure coordinates of the molecule or molecular complex define the same relative spatial configuration as at least a portion of the atomic coordinates corresponding to Glu 48, Asp 49, Asp 56, Glu 57, Asp 58, Glu 64, Glu 69 of the epsilon chain of CD3εγ as set out in figure 5.

69. A method according to any one of claims 63 to 66 wherein in step (a) at least a portion of the structure coordinates of the molecule or molecular complex define the same relative spatial configuration as at least a portion of the atomic coordinates conesponding to : Gln 1, Ser 2, Lys 4, Asn 6, Tyr 12, Asp 13, Ala 14, Glu 16, Asp 17, Thr 23, Asp 25, Glu 27, Ala 28, Lys 29, Asp 36, Lys 38, Thr 44, Glu 45, Asp 46, Lys 47, Lys 48, Lys 49, Asn 51, Ser 54, Ala 56, Lys 57, Asp 58, Arg 60, Lys 66, Ser 68, Gln 69, Asn 70, Lys 71, Lys 73, Arg 80 of the gamma chain of CD3εγ as set out in figure 5.

70. A method according to any one of claims 63 to 66 wherein in step (a) at least a portion of the structure coordinates of the molecule or molecular complex define the same relative spatial configuration as at least a portion of the atomic coordinates conesponding to Lys 35, Lys 38, Lys 57, Arg 60, Lys 66, Lys 71, Lys 73 of the gamma chain of CD3εγ as set out in figure 5.

71. A method according to any one of claims 63 to 66 wherein in step (a) at least a portion of the structure coordinates of the molecule or molecular complex define the same relative spatial configuration as at least a portion of the atomic coordmates conesponding to Glu34, Gly46, Glu48, Arg79, GlyδO, Serδl, Lysδ2, Proδ3, Asp δ5 of the epsilon chain of CD3εγ as set out in figure 5.

72. A method according to any one of claims 63 to 66 wherein in step (a) at least a portion of the structural coordinates of the molecule or molecular complex define the same relative spatial configuration as at least a portion of the structure coordinates in figure 5 of the atoms of CD3ε listed in table 1.

73. A method according to any one of claims 63 to 72 wherein the agent is then screened using a biological assay to determine if the compound binds to the CD3εγ in vivo and/or in vitro.

74. A computer-assisted method for identifying an agent capable of binding to the binding domain of a CD3εγ including the steps of:

(a) supplying a computer modelling application with a set of structure coordinates of a molecule or molecular complex, at least a portion of the structural coordinates of the molecule or molecular complex being derived from, or defining the same relative spatial configuration as, at least a portion of the atomic coordinates conesponding to Ser30, Tyr 31, Asp 49, Tφ90, and Ser91 of the light chain and Thr33, Tyr50, Asn52, Arg55, Tyr57, Lys74, Tyr99, AsplOl and Tyrl04 of the heavy chain of the OKT3 as set out in figure 5;

(b) supplying the computer modelling application with a set of structure coordinates of an agent; and

(c) computationally determining the structural similarity of the agent with the molecule or molecular complex, wherein a high level of structural similarity of the agent with the molecule or molecular complex is indicative of potential binding to the CD3εγ.

75. A computer-assisted method for designing an agent capable of binding to CD3εγ including:

(a) supplying a computer modelling application with a set of structure coordinates of a molecule or molecular complex, at least a portion of the structural coordinates of the molecule or molecular complex being derived from, or defining the same relative spatial configuration as, at least a portion of the atomic coordinates conesponding to Ser30, Tyr 31, Asp 49, Tφ90, and Ser91 of the light chain and Thr33, Tyr50, Asn52, Arg55, Tyr57, Lys74, Tyr99, AsplOl and Tyrl04 of the heavy chain of the OKT3 as set out in figure 5; (b) supplying the computer modelling application with a set of structure coordinates for an agent;

(c) evaluating the level of structural similarity between the agent and the molecule or molecular complex; (d) structurally modifying the agent to increase the level of structural similarity of the agent with the molecule or molecular complex to yield a set of structure coordinates for a modified agent.

76. A method according to claim 75 wherein steps (c) and (d) are conducted a plurality of times.

77. A computer-assisted method for designing an agent capable of binding to CD3εγ including:

(a) supplying a computer modelling application with a set of structure coordinates of a molecule or molecular complex, at least a portion of the structural coordinates of the molecule or molecular complex being derived from, or defining the same relative spatial configuration as, at least a portion of the atomic coordinates Ser30, Tyr 31, Asp 49, Tφ90, and Ser91 of the light chain and Thr33, Tyr50, Asn52, Arg55, Tyr57, Lys74, Tyr99, AsplOl and Tyrl04 of the heavy chain of the OKT3 as set out in figure 5 ;

(b) computationally building a model of an agent represented by a set of structure coordinates; and

(c) determining the level of structural similarity of the agent with the molecule or molecular complex, wherein a high level of structural similarity is indicative of potential binding to the CD3εγ.

78. A method according to any one of claims 73 to 77 wherein the agent thus designed is then screened using a biological assay to determine if the compound binds to the CD3εγ in vivo and /or in vitro.