SpringerProtocols: Abstract: An Overview on GPCRs and Drug Discovery: Structure-Based Drug Design and Structural Biology on GPCRs

4. An Overview on GPCRs and Drug Discovery: Structure-Based Drug Design and Structural Biology on GPCRs

By: Kenneth Lundstrom²

Abstract

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G protein-coupled receptors (GPCRs) represent 50–60% of the current drug targets. There is no doubt that this family of membrane proteins plays a crucial role in drug discovery today. Classically, a number of drugs based on GPCRs have been developed for such different indications as cardiovascular, metabolic, neurodegenerative, psychiatric, and oncologic diseases. Owing to the restricted structural information on GPCRs, only limited exploration of structure-based drug design has been possible. Much effort has been dedicated to structural biology on GPCRs and very recently an X-ray structure of the β2-adrenergic receptor was obtained. This breakthrough will certainly increase the efforts in structural biology on GPCRs and furthermore speed up and facilitate the drug discovery process.

Affiliation(s): (2) PanTherapeutics, Lutry, Switzerland

Book Title: G Protein-Coupled Receptors in Drug Discovery

Series: Methods in Molecular Biology | Volume: 552 | Pub. Date: Aug-01-2009 | Page Range: 51-66 | DOI: 10.1007/978-1-60327-317-6_4

Subject: Pharmacology/Toxicology

Key Words: GPCRs - Drug discovery - Overexpression - Functional receptor - X-ray crystallography - Structure-based drug design

References

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1.	Blundel, T.L. (1996) Structure-based drug design. Nature 384S, 23–26.

2.	Stoll, V., Qin, W., Stewart, K.D., Jakob, C., Park, C., Walter, K., Simmer, R.L., Helfrich, R., Bussiere, D., Kao, J., Kempf, D., Sham, H.L., and Norbeck, D.W. (2002) X-ray crystallographic structure of ABT-378 (lopinavir) bound to HIV-1 protease. Bioorg. Med. Chem. 10, 2803–2806.

3.	Varghese, J.N. (1999) Development of neuraminidase inhibitors as anti-influenza virus drugs. Drug Dev. Res. 46, 176–196.

4.	http://www.mpibp-frankfurt.mpg.de/michel/public/memprotstruct.html

5.	Civelli, O., Nothacker, H.P., Saito, Y., Wang, Z., Lin, S.H., and Reinsheid, R.K. (2001) Novel neurotransmitters as natural ligands of orphan G protein-coupled receptors. Trends Neurosci. 24, 230–237.

6.	Cao, W., Luttrell, L.M., Medvedev, A.V., Pierce, K.L., Daniel, K.W., Dixon, T.M., Lefkowitz, R.J., and Collins, S. (2000) Direct binding of activated c-Src to the beta 3-adrenergic receptor is required for MAP kinase activation. J. Biol. Chem. 275, 38131–38134.

7.	Luttrell, L.M., Ferguson, S.S., Daaka, Y., Miller, W.E., Maudsley, S., Della Rocca, G.J., Lin, F., Kawakatsu, H., Owada, K., Luttrell, D.K., Caron, M.G., and Lefkowitz, R.J. (1999) Beta-arrestin-dependent formation of beta2 adrenergic receptor–Src protein kinase complexes. Science 283, 655–661.

8.	Imamura, T., Huang, J., Dalle, S., Ugi, S., Usui, I., Luttrell, L.M., Miller, W.E., Lefkowitz, R.J., and Olefsky, J.M. (2001) Beta-arrestin-mediated recruitment of the Src family kinase Yes mediates endothelin-1-stimulated glucose transport. J. Biol. Chem. 276, 43663–43667.

9.	Marrero, M.B., Schieffer, B., Paxton, W.G., Heerdt, L., Berk, B.C., Delafontaine, P., and Bernstein, K.E. (1995) Direct stimulation of Jak/STAT pathway by the angiotensin II AT1 receptor. Nature 375, 247–250.

10.	Vanti, W.B., Swaminathan, S., Blevins, R., Bonini, J.A., O’Dowd, B.F., and George, S.R. (2001) Patent status of the therapeutically important G protein-coupled receptors. Endocr. Rev. 21, 90–113.

11.	Esbenshade, T.A. (2006) G protein-coupled receptors as targets for drug discovery. In G Protein-Coupled Receptors in Drug Discovery. Lundstrom, K. and Chiu, M. (eds.), CRC Press, Boca Raton, FL, USA, pp. 15–36.

12.	Lundstrom, K. (2006) Latest development in drug discovery on G protein-coupled receptors. Curr. Prot. Pept. Sci. 7, 465–470.

13.	Seifert, R., and Wenzel-Seifert, K. (2002) Constitutive activity of G protein-coupled receptors: cause of disease and common property of wild-type receptors. Naunyn Schmiedebergs Arch. Pharmacol. 366, 381–416.

14.	Hodgson, J. (1992) Receptor screening and the search for new pharmaceuticals. Biotechnology 10, 973–980.

15.	Miraglia, S., Swartzman, E.E., Mellentin-Michelotti, J., Evangelista, L., Smith, C., Gunawan, I.I., Lohman, K., Goldberg, E.M., Manian, B., and Yuan, P.M. (1999) Homogeneous cell- and bead-based assays for high throughput screening using fluorometric microvolume assay technology. J. Biomol. Screen. 4, 193–204.

16.	Jimonet, P., and Jager, R. (2004) Strategies for designing GPCR-focused libraries and screening sets. Curr. Opin. Drug Discov. Develop. 7, 325–333.

17.	Warrior, U., Gopalakrishan, S., Vanhauwe, J., and Burns, D. (2006) High throughput screening assays for G protein-coupled receptors. In G Protein-Coupled Receptors in Drug Discovery. Lundstrom, K. and Chiu, M. (eds.), CRC Press, Boca Raton, FL, USA, pp. 158–189.

18.	Kunapuli, P., Ransom, R., Murphy, K.L., Pettibone, D., Kerby, J., Grimwood, S., Zuck, P., Hodder, P., Lacson, R., Hoffman, I., Inglese, J., and Strulovici, B. (2003) Development of an intact cell reporter gene beta-lactamase assay for G protein-coupled receptors for high-throughput screening. Anal. Biochem. 314, 16–29.

19.	Chen, G., Way, J., Armour, S., Watson, C., Queen, K., Jayawickreme, C.K., Chen, W.J., and Kenakin, T. (2000) Use of constitutive G protein-coupled receptor activity for drug discovery. Mol. Pharmacol. 57, 125–134.

20.	Lundstrom, K. (2006) Latest development in drug discovery on G protein-coupled receptors. Curr. Prot. Peptide Sci. 7, 465–470.

21.	Holenz, J., Merce, R., Diaz, J.L., Guitart, X., Codony, X., Dordal, A., Romero, G., Torrens, A., Mas, J., Andaluz, B., Hernandez, S., Monroy, X., Sanchez, E., Hernandez, E., Perez, R., Cubi, R., Sanfeliu, O., and Buschmann, H. (2005) Medicinal chemistry driven approaches toward novel and selective serotonin 5-HT6 receptor ligands. J. Med. Chem. 48, 1781–1795.

22.	Klabunde, T. and Hessler, G. (2002) Drug design strategies for targeting G protein-coupled receptors. Chem. Bio. Chem. 3, 928–944.

23.	Veber, D.F. In Peptides, Chemistry and Biology: Proceedings of the 12th American Peptide Symposium. Smith, J.A. and Rivier, J.E. (eds.), ESCOM, Leiden, The Netherlands, pp. 3–14.

24.	Flohr, S., Kurz, M., Kostenis, E., Brkovich, A., Fournier, A., and Klabunde, T. (2002) Identification of nonpeptidic urotensin II receptor antagonists by virtual screening based on a pharmacophore model derived from structure–activity relationships and nuclear magnetic resonance studies on urotensin II. J. Med. Chem. 45, 1799–1805.

25.	Marriott, D.P., Dougall, I.G., Meghani, P., Liu, Y.-J., and Flower, D.R. (1999) Lead generation using pharmacophore mapping and three-dimensional database searching: application to muscarinic M(3) receptor antagonists. J. Med. Chem. 42, 3210–3216.

26.	Alfaro-Lopez, J., Okayama, T., Hosohata, K., Davis, P., Porreca, F., Yamamura, H.I., and Hruby, V.J. (1999) Exploring the structure–activity relationships of [1-(4-tert-butyl-3'-hydroxy)benzhydryl-4-benzylpiperazine] (SL-3111), a high-affinity and selective delta-opioid receptor nonpeptide agonist ligand. J. Med. Chem. 42, 5359–5368.

27.	Alexopoulos, K., Panagiotopoulos, D., Mavromoustakos, T., Fatseas, P., Paredes-Carbajal, M.C., Mascher, D., Mihailescu, S., and Matsoukas, J. (2001) Exploring the structure–activity relationships of [1-(4-tert-butyl-3'-hydroxy)benzhydryl-4-benzylpiperazine] (SL-3111), a high-affinity and selective delta-opioid receptor nonpeptide agonist ligand. J. Med. Chem. 44, 328–339.

28.	Neelamkavil, S., Arison, B., Birzin, E., Feng, J.J., Chen, K.H., Lin, A., Cheng, F.C., Taylor, L., Thornton, E.R., Smith, A.B. 3rd, and Hirschmann, R. (2005) Replacement of Phe6, Phe7, and Phe11 of d-Trp8-somatostatin-14 with l-pyrazinylalanine. Predicted and observed effects on binding affinities at hSST2 and hSST4. An unexpected effect of the chirality of Trp8 on NMR spectra in methanol. J. Med. Chem. 16, 4025–4030.

29.	Cramer, R.D., Patterson, D.E., and Brunce, J.D. (1989) Recent advances in comparative molecular field analysis (CoMFA). Prog. Clin. Biol. Res. 291, 161–165.

30.	Kim, K.H., Greco, G., Novellino, E., Silipo, C., and Vittoria A. (1993) Use of the hydrogen bond potential function in a comparative molecular field analysis (CoMFA) on a set of benzodiazepines. J. Comput. Aided Mol. Des. 7, 263–280.

31.	Salama, I., Hocke, C., Utz, W., Prante, O., Boeckler, F., Hübner, H., Kuwert, T., and Gmeiner, P. (2007) Structure-selectivity investigations of D2-like receptor ligands by CoMFA and CoMSIA guiding the discovery of D3 selective PET radioligands. J. Med. Chem. 50, 489–500.

32.	Tropsha, A., and Wang, S.X. (2006) QSAR modeling of GPCR ligands: methodologies and examples of applications. Ernst. Schering. Found. Symp. Proc. 2, 49–73.

33.	Gaillard, P., Carrupt, P.-A., Testa, B., and Schambel, P. (1996) Binding of arylpiperazines, (aryloxy)propanolamines, and tetrahydropyridylindoles to the 5-HT1A receptor: contribution of the molecular lipophilicity potential to three-dimensional quantitative structure–affinity relationship models. J. Med. Chem. 39, 126–134.

34.	Lopez-Rodriguez, M.L., Murcia, M., Benhamu, B., Viso, A., Campillo, M., and Pardo, L. (2002) Benzimidazole derivatives. 3. 3D-QSAR/CoMFA model and computational simulation for the recognition of 5-HT(4) receptor antagonists. J. Med. Chem. 45, 4806–4815.

35.	Wu, C., Decker, E.R., Blok, N., Bui, H., Chen, Q., Raju, B., Bourgoyne, A.R., Knowles, V., Biediger, R.J., Market, R.V., Lin, S., Dupré, B., Kogan, T.P., Holland, G.W., Brock, T.A., and Dixon, R.A. (1999) Endothelin antagonists: substituted mesitylcarboxamides with high potency and selectivity for ET(A) receptors. J. Med. Chem. 42, 4485–4499.

36.	Siddiqi, S.M., Pearlstein, R.A., Sanders, L.H., and Jacobsen, K.A. (1995) Comparative molecular field analysis of selective A3 adenosine receptor agonists. Bioorg. Med. Chem. 3, 1331–1343.

37.	Rieger, J.M., Brown, M.L., Sullivan, G.W., Linden, J., and Macdonald, T.L. (2001) Design, synthesis, and evaluation of novel A2A adenosine receptor agonists. J. Med. Chem. 44, 531–539.

38.	Lopez-Rodriguez, M.L., Rosado, M.L., Benhamu, B., Morcillo, M.J., Fernandez, E., and Schaper, K.J. (1997) Synthesis and structure – activity relationships of a new model of arylpiperazines. 2. Three-dimensional quantitative structure–activity relationships of hydantoin-phenylpiperazine derivatives with affinity for 5-HT1A and alpha 1 receptors. A comparison of CoMFA models. J. Med. Chem. 40, 1648–1656.

39.	Forbes, I.T., Dabbs, S., Duckworth, D.M., Ham, P., Jones, G.E., King, F.D., Saunders, D.V., Blaney, F.E., Naylor, C.B., Baxter, G.S., Blackburn, T.P., Kennett, G.A., and Wood, M.D. (1996) Synthesis, biological activity, and molecular modeling of selective 5-HT(2C/2B) receptor antagonists. J. Med. Chem. 39, 4966–4977.

40.	Bromidge, S.M., Dabbs, S., Davies, D.T., Duckworth, D.M., Forbes, I.T., Ham, P., Jones, G.E., King, F.D., Saunders, D.V., Starr, S., Thewlis, K.M., Wyman, P.A., Blaney, F.E., Naylor, C.B., Bailey, F., Blackburn, T.P., Holland, V., Kennett, G.A., Riley, G.J., and Wood, M.D. (1998) Novel and selective 5-HT2C/2B receptor antagonists as potential anxiolytic agents: synthesis, quantitative structure–activity relationships, and molecular modeling of substituted 1-(3-pyridylcarbamoyl)indolines. J. Med. Chem. 41, 1598–1612.

41.	Shacham, S., Topf, M., Avisar, N., Glaser, F., Marantz, Y., Bar-Haim, S., Noiman, S., Naor, Z., and Becker, O.M. (2001) Modeling the 3D structure of GPCRs from sequence. Med. Res. Rev. 21, 472–483.

42.	Bissantz, C., Bernard, P., Hibert, M., and Rognan D. (2003) Protein-based virtual screening of chemical databases. II. Are homology models of G protein-coupled receptors suitable targets? Proteins 50, 5–25.

43.	Shacham, S., Marantz, Y., Bar-Haim, S., Kalid, O., Warshaviak, D., Avisar, N., Inbal, B., Heifetz, A., Fichman, M., Topf, M., Naor, Z., Noiman, S., and Becker, O.M. (2004) PREDICT modeling and in-silico screening for G protein-coupled receptors. Proteins 57, 51–86.

44.	Sirois, S., Hatzakis, G., Wei, D., Du, Q., and Chou, K.C. (2005) Assessment of chemical libraries for their druggability. Comput. Biol. Chem. 29, 55–67.

45.	Milligan, G. (2004) G protein-coupled receptor dimerization: function and ligand pharmacology. Mol. Pharmacol. 66, 1–7.

46.	Jones, K.A., Borowsky, B., Tamm, J.A., Craig, D.A., Durkin, M.M., Dai, M., Yao, W.J., Johnson, M., Gunwaldsen, C., Huang, L.Y., Tang, C., Shen, Q., Salon, J.A., Morse, K., Laz, T., Smith, K.E., Nagarathnam, D., Noble, S.A., Branchek, T.A., and Gerald, C. (1998) GABA(B) receptors function as a heteromeric assembly of the subunits GABA(B)R1 and GABA(B)R2. Nature 396, 674–679.

47.	Li, X., Staszewski, L., Xu, H., Durick, K., Zoller, M., and Adler, E. (2002) Human receptors for sweet and umami taste. Proc. Natl. Acad. Sci. USA 99, 4692–4696.

48.	Zhao, G.Q., Zhang, Y., Hoon, M.A., Chandrashekar, J., Erlenbach, I., Ryba, N.J., and Zuker, C.S. (2003) The receptors for mammalian sweet and umami taste. Cell 115, 255–266.

49.	Baneres, J.L., and Parello, J. (2003) Structure-based analysis of GPCR function: evidence for a novel pentameric assembly between the dimeric leukotriene B4 receptor BLT1 and the G protein. J. Mol. Biol. 329, 815–829.

50.	Tallman, J. (2000) Dimerization of G protein-coupled receptors: implications for drug design and signaling. Neuropsychopharmacology 23, S1–S2.

51.	George, S.R., O’Dowd, B.F., and Lee, S.P. (2002) G protein-coupled receptor oligomerization and its potential for drug discovery. Nat. Rev. Drug Discov. 1, 808–820.

52.	Civelli, O. (2005) In G Protein-coupled Receptors in Drug Discovery. Lundstrom, K. and Chiu, M.(eds.), CRC Press, Boca Rotan, FL, USA, pp. 337–356.

53.	Koster, A., Montkowski, A., Schulz, S., Stube, E.M., Knaudt, K., Jenck, F., Moreau, J.L., Nothacker, H.P., Civelli, O., and Reinscheid, R.K. (1999) Targeted disruption of the orphanin FQ/nociceptin gene increases stress susceptibility and impairs stress adaptation in mice. Proc. Natl. Acad. Sci. USA 96, 10444–10449.

54.	Chemelli, R.M., Willie, J.T., Sinton, C.M., Elmquist, J.K., Scammell, T., Lee, C., Richardson, J.A., Williams, S.C., Xiong, Y., Kisanuki, Y., Fitch, T.E., Nakazato, M., Hammer, R.E., Saper, C.B., and Yanagisawa, M. (1999) Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 98, 437–451.

55.	Sakurai, T., Amemiya, A., Ishii, M., Matsuzaki, I., Chemelli, R.M., Tanaka, H., Williams, S.C., Richardson, J.A., Kozlowski, G.P., Wilson, S., Arch, J.R., Buckingham, R.E., Haynes, A.C., Carr, S.A., Annan, R.S., McNulty, D.E., Liu, W.S., Terrett, J.A., Elshourbagy, N.A., Bergsma, D.J., and Yanagisawa, M. (1998) Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 92, 573–585.

56.	Nakazato, M., Murakami, N., Date, Y., Kojima, M., Matsuo, H., Kangawa, K., and Matsukura, S. (2001) A role for ghrelin in the central regulation of feeding. Nature 409, 194–198.

57.	Ohtaki, T., Shintani, Y., Honda, S., Matsumoto, H., Hori, A., Kanehashi, K., Terao, S., Kumano, S., Takatsu, Y., Masuda, Y., Ishibashi, Y., Watanabe, T., Asada, M., Yamada, T., Suenaga, M., Kitada, C., Usuki, S., Kurokawa, T., Onda, H., Nishimura, O., and Fujino, M. (2001) Metastasis suppressor gene KiSS-1 encodes peptide ligand of a G protein-coupled receptor. Nature 411, 613–617.

58.	Lundstrom, K. (2006) Biology of G protein-coupled receptors. In G Protein-Coupled Receptors in Drug Discovery. Lundstrom, K. and Chiu, M. (eds.), CRC Press, Boca Raton, FL, USA, pp. 3–14.

59.	Spirin, A.S., Baranov, V.I., Ryabova, L.A., Ovodov, S.Y., and Alakhov, Y.B. (1988) A continuous cell-free translation system capable of producing polypeptides in high yield. Science 242, 1162–1164.

60.	Klammt, C., Lohr, F., Schafer, B., Haase, W., Dotsch, V., Ruterjans, H., Glaubitz, C., and Bernhard, F. (2004) High level cell-free expression and specific labeling of integral membrane proteins. Eur. J. Biochem. 271, 568–580.

61.	Lundstrom, K., Wagner, R., Reinhart, C., Desmyter, A., Cherouati, N., Magnin, T., Zeder-Lutz, G., Courtot, M., Prual, C., André, N., Hassaine, G., Michel, H., Cambillau, C., and Pattus, F. (2006) Structural genomics on membrane proteins: comparison of more than 100 GPCRs in 3 expression systems. J. Struct. Funct. Genomics 7, 77–91.

62.	Luca, S., White, J.F., Sohal, A.K., Filippov, D.V., van Boom, J.H., Grisshammer, R., and Baldus, M. (2003) The conformation of neurotensin bound to its G protein-coupled receptor. Proc Natl Acad Sci USA 100, 10706–10711.

63.	Kiefer, H. (2003) In vitro folding of alpha-helical membrane proteins. Biochim. Biophys. Acta 1610, 57–62.

64.	Weiss, H.M., and Grisshammer, R. (2002) Purification and characterization of the human adenosine A2a receptor functionally expressed in Escherichia coli. Eur. J. Biochem. 269, 82–92.

65.	Grisshammer, R., White, J.F., Trinh, L.B., and Shiloach, J. (2005) Large-scale expression and purification of a G protein-coupled receptor for structure determination – an overview. J. Struct. Funct. Genomics 6, 159–163.

66.	Winter-Vann, A.M., Martinez, L., Bartus, C., Levay, A., and Turner, G.J. (2001) G protein-coupled expression in Halobacterium salinarum. In Perspectives on Solid State NMR in Biology. Kuehne, S.R. and de Groot, H. (eds.), Doordrecht, Kluwer, The Netherlands, pp. 141–159.

67.	Kunji, E.R., Slotboom, D.J. and Poolman, B. (2003) Lactococcus lactis as host for overproduction of functional membrane proteins. Biochim. Biophys. Acta 1610, 97–108.

68.	David, N.E., Gee, M., Andersen, B., Naider, F., Thorner, J., and Stevens, R.C. (1997) Expression and purification of the Saccharomyces cerevisiae alpha-factor receptor (Ste2p), a 7-transmembrane-segment G protein-coupled receptor. J. Biol. Chem. 272, 15553–15561.

69.	Andersen, B., and Stevens, R.C. (1998) The human D1A dopamine receptor: heterologous expression in Saccharomyces cerevisiae and purification of the functional receptor. Protein Expr. Purif. 13, 111–119.

70.	Weiss, H.M., Haase, W., Michel, H., and Reilander, H. (1998) Comparative biochemical and pharmacological characterization of the mouse 5HT5A 5-hydroxytryptamine receptor and the human beta2-adrenergic receptor produced in the methylotrophic yeast Pichia pastoris. Biochem. J. 330, 1137–1147.

71.	André, N., Cherouati, N., Prual, C., Steffan, T., Zeder-Lutz, G., Magnin, T., Pattus, F., Michel, H., Wagner, R., and Reinhart, C. (2006) Enhancing functional production of G protein-coupled receptors in Pichia pastoris to levels required for structural studies via a single expression screen. Protein Sci. 15, 1115–1126.

72.	Massotte, D. (2003) G protein-coupled receptor overexpression with the baculovirus-insect cell system: a tool for structural and functional studies. Biochim. Biophys. Acta 1610, 77–89.

73.	Akermoun, M., Koglin, M., Zvalova-Iooss, D., Folschweiller, N., Dowell, S.J., and Gearing, K.L. (2005) Characterization of 16 human G protein-coupled receptors expressed in baculovirus-infected insect cells. Protein Expr. Purif. 44, 65–74.

74.	Reeves, P.J., Callewaert, N., Contreras, R., and Khorana, H.G. (2002) Rhodopsin-HEK structure and function in rhodopsin: high-level expression of rhodopsin with restricted and homogeneous N-glycosylation by a tetracycline-inducible N-acetylglucosaminyltransferase I-negative HEK293S stable mammalian cell line. Proc. Natl. Acad. Sci. USA 99, 13419–13424.

75.	Lundstrom, K. (2003) Semliki Forest virus vectors for rapid and high-level expression of integral membrane proteins. Biochim. Biophys. Acta 1610, 90–96.

76.	Hassaine, G., Wagner, R., Kempf, J., Cherouati, N., Hassaine, N., Prual, C., André, N., Reinhart, C., Pattus, F., and Lundstrom, K. (2006) Semliki Forest virus vectors for overexpression of 101 G protein-coupled receptors in mammalian host cells. Protein Expr. Purif. 45, 343–351.

77.	Henderson, R., Baldwin, J.M., Ceska, T.A., Zemlin, F., Beckmann, E., and Downing, K.H. (1990) Model for the structure of bacteriorhodopsin based on high-resolution electron cryo-microscopy. J. Mol. Biol. 213, 899–929.

78.	Palczewski, K., Kumasaka, T., Hori, T., Behnke, C.A., Motoshima, H., Fox, B.A., Le Trong, I., Teller, D.C., Okada, T., Stenkamp, R.E., Yamamoto, M., and Miyano, M. (2000) Crystal structure of rhodopsin: a G protein-coupled receptor. Science 289, 739–745.

79.	Cherezov, V., Rosenbaum, D.M., Hanson, M.A., Rasmussen, S.G., Thian, F.S., Kobilka, T.S., Choi, H.J., Kuhn, P., Weis, W.I., Kobilka, B.K., and Stevens, R.C. (2007) High-resolution crystal structure of an engineered human beta2-adrenergic G protein-coupled receptor. Science 318, 1258–1265.

80.	Rosenbaum, D.M., Cherezov, V., Hanson, M.A., Rasmussen, S.G., Thian, F.S., Kobilka, T.S., Choi, H.J., Yao, X.J., Weis, W.I., Stevens, R.C., and Kobilka, B.K. (2007) GPCR engineering yields high-resolution structural insights into beta2-adrenergic receptor function. Science 318, 1266–1273.

81.	Zhou, W., Flanagan, C., Ballesteros, J.A., Konvicka, K., Davidson, J.S., Weinstein, H., Millar, R.P., and Sealfon, S.C. (1994) A reciprocal mutation supports helix 2 and helix 7 proximity in the gonadotropin-releasing hormone receptor. Mol. Pharmacol. 45, 165–170.

82.	Fong, T.M., Yu, H., Huang, R.R., and Strader, C.D. (1992) The extracellular domain of the neurokinin-1 receptor is required for high-affinity binding of peptides. Biochemistry 31, 11806–11811.

83.	Huang, R.R., Yu, H., Strader, C.D., and Fong, T.M. (1994) Interaction of substance P with the second and seventh transmembrane domains of the neurokinin-1 receptor. Biochemistry 33, 3007–3013.

84.	Gether, U., Johansen, T.E., Snider, R.M., Lowe, J.A. 3rd., Nakanishi, S., and Schwartz, T.W. (1993) Different binding epitopes on the NK1 receptor for substance P and non-peptide antagonist. Nature 362, 345–348.

85.	Sachais, B.S., Snider, R.M., Lowe, J.A. 3rd., and Krause, J.E. (1993) Molecular basis for the species selectivity of the substance P antagonist CP-96,345. J. Biol. Chem. 268, 2319–2323.

86.	Lundstrom, K., Hawcock, A.B., Vargas, A., Ward, P., Thomas, P., and Naylor, A. (1997) Effect of single point mutations of the human tachykinin NK1 receptor on antagonist affinity. Eur. J. Pharmacol. 337, 73–81.

87.	Tota, M.R., Candelore, M.R., Dixon, R.A. and Strader, C.D. (1991) Biophysical and genetic analysis of the ligand-binding site of the beta-adrenoceptor. Trends Pharmacol. Sci. 12, 4–6.

88.	Spedding, M., Newman-Tancredi, A., Millan, M.J., Dacquet, C., Michel, A.N., Jacoby, E., Vickery, B., and Tallentire, D. (1998) Interaction of the anxiogenic agent, RS-30199, with 5-HT1A receptors: modulation of sexual activity in the male rat. Neuropharmacology 37, 769–780.

89.	Trumpp-Kallmeyer, S., Joflack, J., Bruinvels, A., and Hibert, M. (1992) Modeling of G protein-coupled receptors: application to dopamine, adrenaline, serotonin, acetylcholine, and mammalian opsin receptors. J. Med. Chem. 35, 3448–3462.

90.	Schwartz, T.W., and Rosenkilde, M.M. (1996) Is there a “lock” for all agonist “keys” in 7TM receptors? Trends Pharmacol. Sci. 17, 213–216.

91.	Soudijn, W., Van Wijngaarden, I., and Ijzerman, A.P. (2004) Allosteric modulation of G protein-coupled receptors: perspectives and recent developments. Drug Discov. Today 9, 752–758.

92.	Christopoulos, A. (2002) Allosteric binding sites on cell-surface receptors: novel targets for drug discovery. Nat. Rev. Drug Discov. 1, 198–210.

93.	Elling, C.E., and Schwartz, T.W. (1996) Connectivity and orientation of the seven helical bundle in the tachykinin NK-1 receptor probed by zinc site engineering. EMBO J. 15, 6213–6219.

94.	Thirstrup, K., Elling, C.E., Hjorth, S.A., and Schwartz, T.W. (1996) Construction of a high affinity zinc switch in the kappa-opioid receptor. J. Biol. Chem. 271, 7875–7878.

95.	Zeng, F.Y., Hopp, A., Soldner, A., and Wess, J. (1999) Use of a disulfide cross-linking strategy to study muscarinic receptor structure and mechanisms of activation. J. Biol. Chem. 274, 16629–16640.

96.	Turcatti, G., Nemeth, K., Edgerton, M.D., Meseth, U., Talabot, F., Peitsch, M., Knowles, J., Vogel, H., and Chollet, A. (1996) Probing the structure and function of the tachykinin neurokinin-2 receptor through biosynthetic incorporation of fluorescent amino acids at specific sites. J. Biol. Chem. 271, 19991–19998.

97.	Altenbach, C., Cai, K., Khorana, H.G., and Hubbell, W.L. (1999) Structural features and light-dependent changes in the sequence 306-322 extending from helix VII to the palmitoylation sites in rhodopsin: a site-directed spin-labeling study. Biochemistry 38, 7931–7937.

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