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EP1090119A2 - Reruchrezeptoren und deren verwendung - Google Patents

Reruchrezeptoren und deren verwendung

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Publication number
EP1090119A2
EP1090119A2 EP99957168A EP99957168A EP1090119A2 EP 1090119 A2 EP1090119 A2 EP 1090119A2 EP 99957168 A EP99957168 A EP 99957168A EP 99957168 A EP99957168 A EP 99957168A EP 1090119 A2 EP1090119 A2 EP 1090119A2
Authority
EP
European Patent Office
Prior art keywords
receptor
receptors
sequences
host
olfactory
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP99957168A
Other languages
English (en)
French (fr)
Inventor
Jean-Luc Clement
Alain Tirard
Marielle Renucci
Anne Belaich
Valéry MATARAZZO
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Centre National de la Recherche Scientifique CNRS
Original Assignee
Centre National de la Recherche Scientifique CNRS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Centre National de la Recherche Scientifique CNRS filed Critical Centre National de la Recherche Scientifique CNRS
Publication of EP1090119A2 publication Critical patent/EP1090119A2/de
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants

Definitions

  • the present invention relates to the discovery of new olfactory receptors in the groundhog, to the cloning and sequencing of the genes coding for these receptors as well as to the use thereof for the screening of ligands and the preparation of biosensors. .
  • odors are the result of a complex combination of several molecules. This complexity raises interesting questions about the characteristics of receptors to allow animals to recognize a myriad of odorous molecules (estimated at more than 10,000) at concentrations as low as 10 -12 M. It seems that recognition is based on a large multigene family of odor receptors comprising several hundreds or thousands of subtypes. These receptors are supposed to contain 7 trans-membrane domains, based on the hypothesis that odorous signals are transduced by cascades of reactions coupled to G proteins in sensory olfactory neurons. Transduction results in an increase in second messengers such as cyclic nucleotides or inositol triphosphate and in turn these messengers activate the ion-dependent channels and the phosphorylation of several proteins including the odor receptors themselves.
  • second messengers such as cyclic nucleotides or inositol triphosphate
  • Buck and Axel (3) first characterized rat odor receptors using amplification techniques (PCR) and degenerate primers corresponding to the most conserved domains of receptors coupled to G proteins. Since these early works, more than 339 receptors have been sequenced, most often partially, from a wide variety of species including humans, dogs, mice, chicken, two species of fish, two species of amphibians and a nematode. Many species remain to be studied, however, and it is estimated that more than 1,000 genes (or 1% of the genome) code for the olfactory receptor superfamily. The mechanisms underlying olfactory perception are singular and unique in comparison with other sensory systems and further study in this area which has important implications for the identification of these proteins is necessary.
  • PCR amplification techniques
  • oligonucleotides corresponding to the sequence of domains conserved in the second transmembrane domain, the second intracellular loop and the 7th transmembrane domain of olfactory receptors were used in pairs as primers for PCR from the complementary DNA obtained using 1 ′ Groundhog nasal epithelium mRNA.
  • the invention therefore relates to a purified groundhog olfactory receptor.
  • the distinction between tens of thousands of odors depends on a myriad of receptors located on the surface of the neuronal dendrites of the nasal epithelium.
  • the inventors Using the alpine marmot nasal epithelium and different sets of degenerate primers corresponding to consensus sequences of odor receptors, the inventors managed to amplify by reverse PCR (RT-PCR), clone and obtain the sequence partial of 23 new gene products encoding odor receptors.
  • RT-PCR reverse PCR
  • the invention therefore relates more particularly to a purified olfactory receptor constituted by or comprising the amino acid sequence chosen from those represented in the sequence list in the appendix under the numbers SEQ ID No: 1 to SEQ ID No: 23, or a functionally derived derivative equivalent of these.
  • equivalent derivative of these sequences is meant the sequences comprising a modification and / or a deletion and / or an addition of one or more amino acid residues but retaining approximately 75% and preferably at least 95% homology with the sequence from which it is derived.
  • the receptors of the invention have very conserved regions and very heterogeneous regions. It is considered that the very conserved regions are those which confer on the protein its receptor character, while the very heterogeneous regions are those which confer on each receptor its specificity. Thus, depending on the application envisaged, it is possible to prepare derivatives of the receptors of the invention whose specificity is modified but which remain within the scope of the present invention.
  • the subject of the invention is also poly or monoclonal antibodies directed against at least one receptor of the invention, a derivative or a fragment thereof.
  • These antibodies can be prepared by the methods described in the literature.
  • Polyclonal antibodies are formed according to conventional techniques by injecting proteins, extracted from epithelium or produced by genetic transformation of a host, in animals, then recovery of antisera and antibodies from antisera, for example by chromatography. 'affinity.
  • Monoclonal antibodies can be produced by fusing myeloma cells with spleen cells from animals previously immunized using the receptors of the invention. These antibodies are useful for searching for new olfactory receptors or the homologs of these receptors in other mammals or also for studying the relationship between receptors of different individuals or species.
  • the invention also relates to a nucleic acid molecule comprising or consisting of a nucleic sequence coding for a receptor as defined above. More particularly, the invention relates to a nucleic acid molecule comprising or consisting of a sequence chosen from those represented in the list of sequences in the appendix under the numbers SEQ ID No: 24 to SEQ ID No: 47, which code respectively for receptors whose amino acid sequences are represented in the sequence list in the appendix under the numbers SEQ ID No: 1 to SEQ ID No: 23.
  • the invention obviously also relates to the nucleotide sequences derived from the above sequences, for example due to the degeneracy of the genetic code, and which codes for proteins having characteristics and properties of olfactory receptors.
  • the invention also relates to a vector comprising at least one preceding nucleic acid molecule, advantageously associated with suitable control sequences, as well as a method of production or expression in a cellular host of a receptor of the invention. or a fragment of it.
  • the preparation of these vectors as well as the production or expression in a host of the proteins of the invention can be carried out by the techniques of molecular biology and genetic engineering well known to those skilled in the art.
  • a method for producing a receptor according to the invention consists in: transferring a nucleic acid molecule of the invention or a vector containing said molecule in a cellular host,
  • a method of expression of a receptor according to the invention consists in: transferring a nucleic acid molecule of the invention or a vector containing said molecule in a cellular host,
  • the cell host used in the above methods can be chosen from prokaryotes or eukaryotes and in particular from bacteria, yeasts, mammalian, plant or insect cells.
  • a nucleic acid molecule encoding an olfactory receptor or a vector according to the invention can also be used to transform animals and establish a line of transgenic animals.
  • the vector used is chosen according to the host to which it will be transferred; it can be any vector such as a plasmid.
  • the invention therefore also relates to cellular hosts expressing olfactory receptors obtained in accordance with the preceding methods.
  • the invention also relates to the nucleic acid probes and oligonucleotides prepared from the nucleic acid molecules of the invention.
  • probes are useful for the detection by hybridization of similar receptor sequences in other individuals or species.
  • these probes are brought into contact with a biological sample.
  • Different hybridization techniques can be implemented such as spot hybridization (Dot-blot) or hybridization on replicas (Southern technique) or other techniques (DNA chips).
  • Dot-blot spot hybridization
  • Southern technique hybridization on replicas
  • DNA chips DNA chips
  • the olfactory receptors are proteins with 7 transmembrane domains coupled with G proteins. of a ligand on the receptor causes a change in conformation of the receptor, and inside the cell, this signal is transduced via second messengers. Consequently, the subject of the invention is a method for screening for compounds capable of constituting ligands for the receptors described above, consisting in bringing a compound into contact with one or more of said receptors and in measuring by any appropriate means the affinity between said compound. and said receiver.
  • the contact between the compound to be tested and the olfactory receptor (s) of the invention can be carried out using hosts described above and expressing on their surface at least said receptors. It may be a line of immortalized olfactory cells or not, transfected with a vector carrying 1 ⁇ DNc making it possible to express on its surface and at a high level a functional recombinant olfactory receptor. If the test compound constitutes a ligand, bringing it into contact with transformed cells induces intracellular signals which result from the binding of said compound to the receptor.
  • the contacting of the compounds to be tested with the receptors of the invention can also be carried out by fixing one or more receptors on one or more membranes.
  • the olfactory receptors of the invention can therefore also be integrated into a biosensor. In such a system, it is possible to visualize in real time interactions between the test compound and the receptor.
  • One of the partners of the receptor / ligand couple is attached to an interface which may contain a matrix covered with aliphatic chains. This hydrophobic matrix can be easily covered with a lipid layer by spontaneous fusion of liposomes injected in contact with it. Olfactory receptors inserted into liposomes or vesicles can thus be integrated into biosensors.
  • the ligands are thus analyzed with respect to one or more different olfactory receptors.
  • the above methods are used to determine whether a compound activates or inhibits receptors.
  • the invention therefore also relates to a compound not yet known constituting a ligand of an olfactory receptor, identified and selected by the above method.
  • FIG. 2 shows the alignment of 14 of the 23 putative groundhog olfactory receptor sequences. 14 different sequences (AMOR 1 to AMOR 14) were analyzed using Clustalw software. The shaded regions indicate the consensus domains containing the amino acids almost (.) Or totally (*) conserved. The transmembrane domains (DU to
  • FIG. 3 represents the hydropathy profiles of the long sequences obtained with the primer set ct (AMOR 1 to AMOR 7) and the short sequences obtained with the primer set 3-2 (AMOR 8 to AMOR 14) were obtained as described in Material and Methods
  • the long sequences contain 6 regions of strong hydrophobicity (peaks) separated by 5 more hydrophilic valleys.
  • the short sequences have only 4 regions of high hydrophobicity and 3 hydrophilic regions.
  • FIG. 4 represents the analysis of the variability of the 14 new uninterrupted marmot olfactory receptor sequences.
  • FIG. 5 represents a dendrogram showing the similarities between olfactory receptors of different species.
  • the olfactory receptor sequences of other species come from the NCBI database. There are five families (noted on the left). The asterisks indicate the sequences for which the percentage of similarity between species exceeds 70%.
  • H male; F: fish; C: chicken; N: nematode; B: bee; A: amphibians; D: dog; M: mouse and MM: groundhog.
  • the olfactory epithelium was taken from a dead wild groundhog. During the dissection, the head was kept frozen in dry ice. The fabrics were kept at -80 ° C until used.
  • the poly (A) + mRNA was transcribed into cDNA using a reverse transcriptase and then amplified by PCR. To increase the production of the first strand of complete cDNA, the cDNA Cycle Kit was used. Reverse transcription was made from 150 ng of poly (A) + mRNA using oligo dT primers or rando pri ers. After extraction with phenol / H2O / EDTA (v / v / v: 1/20/80), the cDNA of the aqueous phase was precipitated in the presence of ammonium acetate and entrained glycogen in glacial ethanol at -80 ° C.
  • Primer 4 5 '-CC (CT) ATG TA (TC) TTI TT (TC) CT (CT) I (GC) (CT) AA (TC) (TC) TI TC.
  • Primer C 5'-CC (CT) ATG TA (TC) TTG TT (TC)
  • CT CT
  • G GC
  • CT CT
  • TC TC
  • TC- TC-
  • Primer 1 5 '- (AG) TT (TC) C (TG) IA (AG) (AG) (CG) (AT) (AG) TA IAT (GA) A (AT) IGG (AG) TT.
  • Primer T 5 '-GCA CTG CAG AT (AG) AAI GG (AG) TTI A (AG) ATI GG.
  • Primer 3 5 '-CAC AAG CTT TIG CIT A (TC) GA (CT) AG (AG) T (TA) (TC) (TCG) TIG C.
  • Primer 2 5' -GCA CTG CAG AT (AG) AAI GG (AG)
  • TTI A (AG) C ATI GG TTI A (AG) C ATI GG.
  • primer combinations have been designed to amplify products of the order of 520 bp.
  • the amplification was carried out in 50 microliters of a solution containing 5 microliters of cDNA, 2 mM dNTP, 100 ⁇ l of each degenerate primer, 1.5 U of Taq polymerase (Boehringer Mannheim, Germany), 50 mM KC1, 2.5 mM MgC12, 10 mM Tris / HCl pH8, 3 and 0.01 gelatin. To avoid evaporation, the surface of the mixture was covered with 35 microliters of mineral oil (Sigma, France).
  • thermocycler Hybaid, Omnigene, USA
  • the PCR was carried out using a thermocycler (Hybaid, Omnigene, USA) according to the following protocol: one cycle at 94 ° C for 90 s, 40 cycles at 94 ° C for 20 s, 50 ° C for 25 s and 72 ° C for 90 s, and a cycle at 72 ° C for 120 s.
  • each white colony was resuspended in 10 microliters of TE buffer.
  • the PCR was carried out in 10 microliters of a solution containing 1 microliters of colony suspension, 3 pmol of each universal primer U19 and T7, 10 mM dNTP, 50 mM KC1 and 2.5 mM MgC12 in a Tris HC1 pH 8 buffer, 3 with 0.25 U of Taq polymerase.
  • the protocol for PCR was as follows: one cycle at 94 ° C for 270 s, 30 cycles at 94 ° C for 30 s, 48 ° C for 30 s and 72 ° C for 50 s, and one cycle at 72 ° C for 120 s.
  • 10 microliters of the reaction product were analyzed on a 2% agarose gel.
  • the positive clones were cultured in liquid LB medium containing 0.1 mg / ml of 1 ampicillin.
  • the plasmid cDNA was extracted and purified using the Wizard miniprep kit (Promega). The samples were sequenced by Génome Express (Grenoble, France).
  • the PCR amplification was carried out with 150 ng of mRNA using the three sets of specific degenerate primers (ct, 4-1, 3-2) described previously in Materials and Methods. Analysis of the electrophoresis carried out with 5 microliter aliquots of the PCR products revealed single bands of the expected size (FIG. 1). With the "T” cDNA, a 520 bp band was obtained with the primers 3-2 and a 720 bp band with the primers ct. With cDNA "R”, a band of 720 bp was obtained using the primers ct. No bands were observed in the other three runways. In the control PCRs, in which a single primer was used, no band of the expected length was observed.
  • the electrophoresis was repeated using the remaining 45 microliters of the sample, and the 550 and 720 bp fragments were extracted. Given the diversity of olfactory receptors, it has been assumed that the population of cDNAs in a band was heterogeneous and therefore no attempt was made to directly sequence the PCR-amplified cDNA fragments. These fragments were cloned into E. coli as described above.
  • the agarose gel electrophoresis of the PCR products showed that 5 R c-t clones, 10 T c-t clones and 22 T 3-2 clones had fragments of the expected size. These 37 positive clones were cultured again for mass production.
  • the average percentage of identical residues was 64%. Seven (AMOR 1-7) of the new marmot sequences were amplified from a pair of primers designed from the transmembrane domains II and VII and are 234 to 237 residues long. Seven other sequences (AMOR 8-14) were obtained with the primers designed from intracellular loop 2 (i2) and the transmembrane domain VII and contain 176 residues. The percentage of identical residues between these 14 new sequences is between 33% (AMOR 4 / AMOR 8) and 79% (AMOR 8 / AMOR 11).
  • the inventors also sought to locate the positions involved in the specific odor binding site by applying an analysis previously introduced for the molecules which bind the antigens.
  • the reasoning is that if these olfactory receptors are supposed to specifically bind odorous molecules, the residues which constitute the specific binding site could show more variability than those which are involved in the core structure and in the signaling function.
  • Figure 4 shows the variability profiles obtained with the alignment of Figure 2. Four peaks of variability are clearly visible.
  • the average hydropathy plot profile shown in parallel indicates that they are not only located within hydrophilic loops as expected (position 210), but also in hydrophobic regions ( eg position 148).
  • the center of the most variable segments is located at positions 30, 100, 148 and 210, the mapping respectively inside the 1st extracytoplasmic loop El, the 4th and 5th transmembrane regions DIV and DV, and the middle of the 3rd loop extracytoplasmic E3.
  • residues at these positions could be involved in the binding site of unknown odor molecules corresponding to these receptors.
  • Figure 5 shows a structural classification of 122 olfactory receptors from the EMBL database found in different species as well as the 14 complete sequences and the 3 incomplete sequences identified in the marmot within the framework of the present invention. With the exception of fish receptors, the receptors are not grouped by species. There are 5 families containing a varied number of receptors. Groundhog olfactory receptors were classified into subfamilies 1, 2 and 5. 12 sequences were classified into subfamily 2.
  • Olfactory receptors include a large multigene family. Their study requires a combination of approaches. A reverse PCR strategy with several different primers has been implemented in the context of the present invention. This approach has been successful since 28 putative sequences of olfactory receptors, 14 of which could allow a comparative analysis have been obtained. It is possible to obtain more sequences by simply changing the PCR conditions.
  • the family of genes cloned in the context of the present invention codes for olfactory receptors for two reasons. On the one hand, the hydropathy profiles of the sequences are in agreement with the receptors for the superfamily of receptors with seven transmembrane domains.
  • the presence of a deep binding site in the transmembrane calyx is not a specific characteristic of the receptor olfactory receptors but is common among receptors with 7 transmembrane domains of biogenic amines.
  • the main site of interaction between receptors with 7 transmembrane domains and the related protein G is the third intracellular loop.
  • the most conserved segment is located between positions 180 to 193, ie the end of this loop and the beginning of the 6th transmembrane domain.
  • the results obtained indicate a remarkable analogy between the marmot olfactory receptor and the rat olfactory receptor.
  • the length (18 residues) of the 3rd intracellular loop (i3) was short.
  • the IVSSI consensus sequence (or a close sequence) was at the N-terminus of the 3rd intracellular loop in 75% of the clones of the invention.
  • the third intracellar loop is rich in Serine residues and can therefore constitute phosphorylation sites for GRK.
  • Receivers with 7 transmembrane domains are classified into several groups.
  • the olfactory receptors are supposed to belong to group I, which is characterized by the presence of a DRY sequence strictly conserved on the N-terminal side of i2.
  • the DRY sequence is present in 4 of the clones of the invention but is replaced by a DRF sequence in the remaining 10.
  • a single groundhog olfactory receptor had a similarity percentage of this order with a rat receptor (AM0R14 73%). In general, we found few strong homologies. This discovery could indicate that either the number of olfactory receptors was too small to allow the identification of true orthologous receptors, or the percentage of similarity between orthologous olfactory receptors may become less than 68%.
  • the Alpine marmot (Marmota marmota) was chosen as a model in this study on the assumption that, given the importance of olfaction to survive in nature, olfaction would be strongly developed.
  • the Alpine marmot marks its territory with secretions produced by the jugal glands.
  • the sense of smell is of the greatest importance because this species has a high level of sociability: it lives in family groups formed by a pair of adult breeding residents and their offspring of several successive litters which remain in the natal group until the age of 2 years or more. Each groundhog has a different combination of odor molecules that members of the same group or of a different group can smell.
  • the olfactory system requires a myriad of different receptors. As mammals are generally believed to have about a thousand genes, the clones identified in this study probably represent only part of the family of groundhog olfactory receptors. In addition to the contribution to the number of receptors identified, our results also support the existence of orthologous receptors between species and the notion that the local variability observed in some of the transmembrane domains could be crucial for the specificity of a receptor. How even a thousand receptors could be able to distinguish among the tens of thousands of odors found in nature is not yet clear. Final confirmation of the nature and olfactory specificity of these receptors will not be possible until the entire sequence has been obtained and specific binding with one or more odorous molecules demonstrated.
  • a novel multigene family may encode odorant receptors: a molecular basis for odor recognition. Cell, 65, 175-187.

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  • Micro-Organisms Or Cultivation Processes Thereof (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
  • Investigating Or Analysing Biological Materials (AREA)
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EP99957168A 1998-06-25 1999-06-22 Reruchrezeptoren und deren verwendung Withdrawn EP1090119A2 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR9808094 1998-06-25
FR9808094A FR2780405B1 (fr) 1998-06-25 1998-06-25 Nouveaux recepteurs olfactifs et leurs utilisations
PCT/FR1999/001495 WO1999067282A2 (fr) 1998-06-25 1999-06-22 Recepteurs olfactifs et leurs utilisations

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US (1) US20020132289A1 (de)
EP (1) EP1090119A2 (de)
JP (1) JP2002518035A (de)
AU (1) AU4270799A (de)
CA (1) CA2331200A1 (de)
FR (1) FR2780405B1 (de)
WO (1) WO1999067282A2 (de)

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AU2288501A (en) * 1999-12-30 2001-07-16 Millennium Pharmaceuticals, Inc. 32164 protein, a novel seven transmembrane protein
TW201006846A (en) 2000-03-07 2010-02-16 Senomyx Inc T1R taste receptor and genes encidung same
AU2001286541A1 (en) * 2000-08-17 2002-02-25 Agensys, Inc. Nucleic acids and corresponding proteins entitled phor1-a11 and phor1-f5d6 useful in treatment and detection of cancer
CN1352042A (zh) * 2000-11-10 2002-06-05 上海博德基因开发有限公司 一种新的多肽——嗅觉受体27.61 和编码这种多肽的多核苷酸
TW201022287A (en) 2001-01-03 2010-06-16 Senomyx Inc T1R taste receptors and genes encoding same
WO2002068473A1 (en) * 2001-02-08 2002-09-06 Temple University-Of The Commonwealth System Of Higher Education Biosensor for detecting chemical agents
JP2005510214A (ja) * 2001-10-16 2005-04-21 オートゲン リサーチ プロプライエトリー リミティッド 肥満と２型糖尿病に関連のある差異的に発現する遺伝子
US7674891B2 (en) 2008-08-01 2010-03-09 International Flavors & Fragrances Inc. Nucleic acid molecules encoding GPR84
US9901551B2 (en) 2009-04-20 2018-02-27 Ambra Bioscience Llc Chemosensory receptor ligand-based therapies
BRPI1013856A2 (pt) 2009-04-20 2016-04-05 Elcelyx Therapeutics Inc terapias à base de ligantes de receptores quimiossensíveis
US8828953B2 (en) 2009-04-20 2014-09-09 NaZura BioHealth, Inc. Chemosensory receptor ligand-based therapies
US9486463B2 (en) 2010-10-19 2016-11-08 Ambra Bioscience Llc Chemosensory receptor ligand-based therapies
AU2012204162B2 (en) 2011-01-07 2017-04-20 Anji Pharmaceuticals Inc. Chemosensory receptor ligand-based therapies
WO2013158928A2 (en) 2012-04-18 2013-10-24 Elcelyx Therapeutics, Inc. Chemosensory receptor ligand-based therapies
JP6449157B2 (ja) * 2013-08-09 2019-01-09 国立大学法人 東京大学 ムスク系香料のスクリーニング方法
JP6926041B2 (ja) 2018-09-12 2021-08-25 株式会社東芝 ケミカルセンサ及び標的物質検出方法
CN109803010A (zh) * 2019-01-12 2019-05-24 天津大学 一种基于仿生学、大数据和基因工程技术实现气味远程传输的方法

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EP0578784A4 (de) * 1991-04-05 1994-11-02 Univ Columbia Gerüchesrezeptoren und ihre anwendungen.
AU1118197A (en) * 1995-11-09 1997-05-29 Johns Hopkins University School Of Medicine, The Novel sperm receptors

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AU4270799A (en) 2000-01-10
JP2002518035A (ja) 2002-06-25
WO1999067282A3 (fr) 2000-04-27
FR2780405A1 (fr) 1999-12-31
FR2780405B1 (fr) 2001-12-28
CA2331200A1 (fr) 1999-12-29
WO1999067282A2 (fr) 1999-12-29
US20020132289A1 (en) 2002-09-19

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