1. Fredriksson, R., Lagerstrom, M.C., Lundin, L.-G., Schioth, H.B. (2003) The G-protein-coupled receptors in the human genome form five main families. Phylo-genetic analysis, paralogon groups, and fingerprints. Mol Pharmacol. 63,1256-1272.

2. Strachan, R.T., Ferrara, G., Roth, B.L. (2006) Screening the receptorome: An efficient approach for drug discovery and target validation. Drug Discov Today. 11, 708-716.

3. Surgand, J.S., Rodrigo, J., Kellenberger, E., Rognan, D. (2006) A chemogenomic analysis of the transmembrane binding cavity of human G-protein-coupled receptors. Proteins. 62, 509-538.

4. Jacoby, E. (2006) Designing compound libraries targeting GPCRs. Ernst Schering Found Symp Proc. 2 , 93 - 103 .

5. Oliveira, L., Hulsen, T., Hulsik, D.L., Paiva, A.C.M., Vriend, G. (2004) Heavier-than-air flying machines are impossible. FEBS Lett. 564, 269-273.

6. Bissantz, C., Wolfgang, C.S., Stahl, G.M. (2005) Focused library design in GPCR projects on the example of 5-HT2c agonists: Comparison of structure-based virtual screening with ligand-based search methods. Proteins. 61, 938-952.

7. Evers, A., Hessler, G., Matter, H., Klabunde,T. (2005) Virtual screening of biogenic amine-binding G-protein coupled receptors: Comparative evaluation of protein-and ligand-based virtual screening protocols. J Med Chem. 48, 5448-5465.

8. Sale, K., Faulon, J.-L., Gray, G.A., Schoeniger, J.S., Young, M.M. (2004) Optimal bundling of transmembrane helices using sparse distance constraints. Protein Sci. 13 , 2613 - 2627 .

9. 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., Becker, O.M. (2004) PREDICT modeling and in-silico screening for G-protein coupled receptors. Proteins. 57 , 51 - 86 .

10. Vaidehi , N. , Floriano, W.B. , Trabanino, R. , Hall , S.E. , Freddolino, P. , Choi , E.J. , Zamanakos, G., Goddard III, W.A. (2002) Prediction of structure and function of G protein-coupled receptors. Proc Natl Acad Sci US A. 99,12622-12627.

11. Zhang, Y., DeVries, M.E., Skolnick, J. (2006) Structure modeling of all identified G protein coupled receptors in the human genome. PLoS Comput Biol. 2, e13.

12. Rosenbaum, D.M., Cherezov, V., Hanson, M.A., Rasmussen, S.G.F., Thian, F.S., Kobilka,T.S., Choi, H.-J., Yao, X.-J., Weis, W.I., Stevens, R.C., Kobilka, B.K. (2007) GPCR engineering yields high-resolution structural insights into ß2-adrenergic receptor function . Science. 318, 266-273.

13. Rasmussen, S.G.F., Choi, H.-J., Rosenbaum, D.M., Kobilka, T.S., Thian, F.S., Edwards, P.C., Burghammer, M., Ratnala, V.R.P., Sanishvili, R., Fischetti, R.F., Schertler, G.F.X., Weis, W.I., Kobilka, B.K. (2007) Crystal structure of the human ß2 adrenergic G-protein-coupled receptor. Nature. 450, 383-387.

14. Cherezov, V., Rosenbaum, D.M., Hanson, M.A., Rasmussen, S.G.F., Thian, F.S., Kobilka, T.S., Choi, H.-J., Kuhn, P., Weis, W.I., Kobilka, B.K., Stevens, R.C. (2007) High-resolution crystal structure of an engineered human ß2-adrenergic G protein coupled receptor. Science. 318,1258-1265.

15. Warne, T., Serrano-Vega, M.J., Baker, J.G., Moukhametzianov, R., Edwards, P.C., Henderson, R., Leslie, A.G., Tate, C.G., Schertler, G.F. (2008) Structure of a ß1-adrenergic G-protein-coupled receptor. Nature. 454,486-491.

16. Jaakola , V.P. , Griffith , M.T. , Hanson , M.A. , Cherezov, V. , Chien , E.Y. , Lane, J.R. , Ijzerman , A.P. , Stevens, R.C. ( 2008 ) The 2.6 angstrom crystal structure of a human A2A adenosine receptor bound to an antagonist. Science. 322 , 1211 - 1217 .

17. Audet, M., Bouvier, M. (2008) Insights into signaling from the ß2-adrenergic receptor structure. Nat Chem Biol. 4, 397-403.

18. Hanson, M., Cherezov, V., Roth, C., Griffith, M., Jaakola, V., Chien, E., Velasquez, J., Kuhn, P., Stevens, R. (2008) A specific cholesterol binding site is established by the 2.8 A structure of the human ß2-adrenergic receptor. Structure. 16, 897-905.

19. Kleywegt, G.J. (2007) Separating model optimization and model validation in statistical cross-validation as applied to crystallography. Acta Crystallogr D Biol Crystallogr. 63 , 939 - 940 .

20. Kleywegt, G.J. (2007) Crystallographic refinement of ligand complexes. Acta Crystallogr D Biol Crystallogr. 63 , 94 - 100 .

Weichenberger, C.X., Sippl, M.J. (2007) NQ-Flipper: Recognition and correction of erroneous asparagine and glutamine side-chain rotamers in protein structures. Nucleic Acids Res. 35, W403-W406.

Katritch, V., Reynolds, K.A., Cherezov, V., Hanson, M.A., Roth, C.B., Yeager, M., Abagyan, R. (2009) Analysis of full and partial agonists binding to b2-adrenergic receptor suggests a role of transmembrane helix V in agonist-specific conformational changes. J Mol Recognit. 22, 307-318.

Abagyan, R., Totrov, M. (1994) Biased probability Monte Carlo conformational searches and electrostatic calculations for peptides and proteins. J Mol Biol. 235, 983 - 1002 .

Kusnetzow, A.K., Altenbach, C., Hubbell, W.L. (2006) Conformational states and dynamics of rhodopsin in micelles and bilayers. Biochemistry. 45 , 5538 - 5550 . Ward, S.D., Hamdan, F.F., Bloodworth, L.M., Siddiqui,N.A., Li, J.H., Wess, J. (2006) Use of an in situ disulfide cross-linking strategy to study the dynamic properties of the cytoplasmic end of transmembrane domain VI of the M3 muscarinic ace-tylcholine receptor. Biochemistry. 45 , 676 - 685 .

Salom, D., Lodowski, D.T., Stenkamp, R.E., Le Trong, I., Golczak, M., Jastrzebska, B., Harris,T., Ballesteros, J.A., Palczewski, K. (2006) Crystal structure of a photo-activated deprotonated intermediate of rhodopsin. Proc Natl Acad Sci U S A. 103, 16123-16128.

Lodowski , D.T. , Salom , D. , Le Trong, I. , Teller, D.C. , Ballesteros, J.A. , Palczewski , K. , Stenkamp, R.E. ( 2007 ) Crystal packing analysis of rhodopsin crystals. J Struct Biol. 158 , 455 - 462 .

Brylinski, M., Skolnick, J. (2008) Q-Dock: Low-resolution flexible ligand docking with pocket - specific threading restraints. J Comput Chem. 29 , 1574 - 1588 . Erickson, J.A., Jalaie, M., Robertson, D.H., Lewis, R.A., Vieth, M. (2004) Lessons in molecular recognition: The effects of ligand and protein flexibility on molecular docking accuracy. J Med Chem. 47 , 45 - 55 .

Totrov, M., Abagyan, R. (2008) Flexible ligand docking to multiple receptor conformations: A practical alternative. Curr Opin Struct Biol. 18 , 178 - 184 . Kufareva, I., Laudet, B., Cochet, C., Abagyan, R. (2008) Structure-based discovery of small molecules that modulate kinase activity by disrupting the subunit interaction: Application to CK2. Protein Sci. 17, 265.

Totrov, M., Abagyan, R. (1997) Flexible protein-ligand docking by global energy optimization in internal coordinates. Proteins. 29, 215-220.

Abagyan, R., Totrov, M., Kuznetsov, D. (1994) ICM—A new method for protein modeling and design: Applications to docking and structure prediction from the distorted native conformation. J Comput Chem. 15 , 488 - 506 .

Totrov, M., Abagyan, R. (1994) Detailed ab initio prediction of lysozyme-antibody complex with 1.6 A accuracy. Nat Struct Mol Biol. 1, 259-263.

Cavasotto, C.N., Abagyan, R.A. (2004) Protein flexibility in ligand docking and virtual screening to protein kinases. J Mol Biol. 337, 209-225.

Totrov, M., Abagyan, R. (1999) Derivation of sensitive discrimination potential for virtual ligand screening. In Proceedings of the 3rd Annual International Conference of Computational Molecular Biology (RECOMB 99). ACM Press, Lyon, France.

Bisson, W.H., Cheltsov, A.V., Bruey-Sedano, N., Lin, B., Chen, J., Goldberger, N.,

May, L.T., Christopoulos, A., Dalton, J.T., Sexton, P.M., Zhang, X.-K., Abagyan, R.

(2007) Discovery of antiandrogen activity of nonsteroidal scaffolds of marketed drugs. Proc Natl Acad Sci U S A. 104,11927-11932.

38. Cavasotto, C.N., Orry, A.J.W., Murgolo, N.J., Czarniecki, M.F., Kocsi, S.A., Hawes, B.E., Neill, K.A., Hine, H., Burton, M.S., Voigt, J.H., Abagyan, R.A., Bayne, M.L., Monsma,F.J. (2008) Discovery of novel chemotypes to a G-protein-coupled receptor through ligand-steered homology modeling and structure-based virtual screening. J Med Chem. 51, 581-588.

39. Christopoulos, A. (2008) Structure-function meets ligand-directed modeling: Towards novel muscarinic receptor chemotypes. Recent Advances in Muscarinic Receptor Pharmacology and Therapeutics. ASPET Symposium, San Diego, CA.

40. Michino, M., Abola, E., Brooks III, C., Dixon, J.S., Moult, J., Stevens, R.C. (2009) Critical assessment of GPCR structure modeling and docking 2008. Nat Rev Drug Discov. 8,455-463.

41. Katritch, V., Rueda, M., Lam, P. C., Yeager, M., Abagyan, R. (2010) GPCR 3D homology models for ligand screening: lessons learned from blind predictions of adenosine A2a receptor complex . Proteins. 78,197-211.

42. Kobilka, B.K. (2007) G protein coupled receptor structure and activation. Biochim Biophys Acta. 1768,794-807.

43. Park, P.S., Lodowski, D.T., Palczewski, K. (2008) Activation of G protein-coupled receptors: Beyond two-state models and tertiary conformational changes. Annu Rev Pharmacol Toxicol. 48,107-141.

44. Park, J.H.,Scheerer,P.,Hofmann,K.P.,Choe,H.-W., Ernst, O.P. (2008) Crystal structure of the ligand-free G-protein-coupled receptor opsin. Nature. 454,183-187.

45. de Graaf, C., Rognan, D. (2008) Selective structure-based virtual screening for full and partial agonists of the beta2 adrenergic receptor. J Med Chem. 51 , 4978 -4985 .

46. Strader, C.D. , Candelore, M.R. , Hill , W.S. , Sigal , I.S. , Dixon , R.A. ( 1989 ) Identification of two serine residues involved in agonist activation of the p-adrenergic receptor. J Biol Chem. 264 , 13572 - 13578 .

47. Ambrosio, C., Molinari, P., Cotecchia, S., Costa,T. (2000) Catechol-binding serines of p (2)-adrenergic receptors control the equilibrium between active and inactive receptor states. Mol Pharmacol. 257,198-210.

48. Liapakis, G., Ballesteros, J.A., Papachristou, S., Chan, W.C., Chen, X., Javitch, J.A. (2000) The forgotten serine. A critical role for Ser-2035.42 in ligand binding to and activation of the p2-adrenergic receptor. J Biol Chem. 275, 37779-37788.

49. Liapakis, G., Chan, W.C., Papadokostaki, M., Javitch, J.A. (2004) Synergistic contributions of the functional groups of epinephrine to its affinity and efficacy at the p2 adrenergic receptor. Mol Pharmacol. 65,1181-1190.

50. Bottegoni, G., Kufareva, I., Totrov, M., Abagyan, R. (2008) A new method for ligand docking to flexible receptors by dual alanine scanning and refinement (SCARE). J Comput Aided Mol Des. 22, 311-325.

51. Bissantz, C., Bernard, P., Hibert, M., 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.

52. Reynolds, K.A. , Katritch , V. , Abagyan , R. ( 2009 ) Identifying conformational changes of the beta(2) adrenoceptor that enable accurate prediction of ligand/

receptor interactions and screening for GPCR modulators. J Comput Aided Mol Des. 23, 273-288.

53. Topiol, S., Sabio, M. (2008) Use of the X-ray structure of the beta2-adrenergic receptor for drug discovery. Bioorg Med Chem Lett. 18,1598-1602.

54. Donnelly, D., Overington, J.P., Blundell,T.L. (1994) The prediction and orientation of {alphaj-helices from sequence alignments: The combined use of environment-dependent substitution tables, Fourier transform methods and helix capping rules. Protein Eng. 7 , 645 - 653 .

55. Freddolino, P.L., Kalani, M.Y.S., Vaidehi, N., Floriano, W.B., Hall, S.E.,Trabanino, R.J., Kam, V.W.T., Goddard III,W.A. (2004) Predicted 3D structure for the human {beta}2 adrenergic receptor and its binding site for agonists and antagonists. Proc Natl Acad Sci U S A. 101, 2736-2741.

56. Kalani , M.Y.S. , Vaidehi , N. , Hall , S.E. , Trabanino, R.J. , Freddolino, P.L. , Kalani, M.A., Floriano, W.B., Kam, V.W.T., Goddard III, W.A. (2004) The predicted 3D structure of the human D2 dopamine receptor and the binding site and binding affinities for agonists and antagonists. Proc Natl Acad Sci U S A. 101, 3815-3820.

57. Becker, O.M., Marantz, Y., Shacham, S., Inbal, B., Heifetz, A., Kalid, O., Bar-Haim, S., Warshaviak, D., Fichman, M., Noiman, S. (2004) G protein-coupled receptors: In silico drug discovery in 3D. Proc Natl Acad Sci U S A. 101,11304-11309.

58. Vaidehi , N. , Schlyer, S. , Trabanino, R.J. , Floriano, W.B. , Abrol , R. , Sharma , S., Kochanny, M., Koovakat, S., Dunning, L., Liang, M., Fox, J.M., de Mendonca, F.L., Pease, J.E., Goddard III, W.A., Horuk, R. (2006) Predictions of CCR1 chemokine receptor structure and BX 471 antagonist binding followed by experimental validation. J Biol Chem. 281, 27613-27620.

59. Elofsson, A., Heijne, G.V. (2007) Membrane protein structure: Prediction versus reality. Annu Rev Biochem. 76,125-140.

60. Ralf, J. ( 2007 ) HCYPRKNDC. Assessment of CASP7 structure predictions for template free targets. Proteins. 69 , 57 - 67 .

61. Trabanino, R.J., Hall, S.E., Vaidehi, N., Floriano, W.B., Kam, V.W.T., Goddard III, W.A. (2004) First principles predictions of the structure and function of G-protein-coupled receptors: Validation for bovine rhodopsin. Biophys J. 86,1904-1921.

62. Zhang, Y., Arakaki, A.K., Skolnick, J. (2005) TASSER: An automated method for the prediction of protein tertiary structures in CASP6. Proteins. 61, 91-98.

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

64. Li, J., Edwards, P.C., Burghammer, M., Villa, C., Schertler, G.F.X. (2004) Structure of bovine rhodopsin in a trigonal crystal form. J Mol Biol. 343,1409-1438.

65. Murakami, M., Kouyama, T. (2008) Crystal structure of squid rhodopsin. Nature. 453, 363-367.

66. Okada, T., Sugihara, M., Bondar, A.-N., Elstner, M., Entel, P., Buss, V. (2004) The retinal conformation and its environment in rhodopsin in light of a new 2.2 A crystal structure. J Mol Biol. 342, 571-583.

67. Standfuss, J., Xie, G., Edwards, P.C., Burghammer, M., Oprian, D.D., Schertler, G.F.X. (2007) Crystal structure of a thermally stable rhodopsin mutant. J Mol Biol. 372 , 1179 - 1188 .

68. White, S. (ed.) (2008) Membrane Proteins ofKnown 3D Structure, Vol. 2008. Irvine: Laboratory at UC Irvine.

69. Patny, A., Desai, P.V., Avery, M.A. (2006) Homology modeling of G-protein-coupled receptors and implications in drug design. Curr Med Chem. 13,1667-1691.

70. An, J.,Totrov, M., Abagyan, R. (2005) Pocketome via comprehensive identification and classification of ligand binding envelopes. Mol Cell Proteomics. 4, 752-761.

71. Costanzi , S. ( 2008 ) On the applicability of GPCR homology models to computer-aided drug discovery: A comparison between in silico and crystal structures of the beta2-adrenergic receptor. J Med Chem. 51, 2907-2914.

72. Avlani,V.A., Gregory,K.J.,Morton, C.J.,Parker, M.W., Sexton, P.M., Christopoulos,

A. (2007) Critical role for the second extracellular loop in the binding of both orthosteric and allosteric G protein-coupled receptor ligands. J Biol Chem. 282 , 25677-25686.

73. Shi , L. , Javitch , J.A. ( 2004 ) The second extracellular loop of the dopamine D2 receptor lines the binding- site crevice. Proc Natl Acad Sci U S A. 101 , 440 - 445 .

74. Rossi, K.A., Weigelt, C.A., Nayeem, A., Krystek Jr., S.R. (2007) Loopholes and missing links in protein modeling. Protein Sci. 16 , 1999 - 2012 .

75. Mehler, E.L., Hassan, S.A., Kortagere, S., Weinstein, H. (2006) Ab initio computational modeling of loops in G-protein-coupled receptors: Lessons from the crystal structure of rhodopsin. Proteins. 64, 673-690.

76. Kortagere, S., Roy, A., Mehler, E. (2006) Ab initio computational modeling of long loops in G-protein coupled receptors. J Comput Aided Mol Des. 20,427-436.

77. Cavasotto, C.N., Orry, A.J.W., Abagyan, R.A. (2003) Structure-based identification of binding sites, native ligands and potential inhibitors for G-protein coupled receptors. Proteins. 51,423-433.

78. de Graaf, C., Foata, N., Engkvist, O., Rognan, D. (2008) Molecular modeling of the second extracellular loop of G-protein coupled receptors and its implication on structure-based virtual screening. Proteins. 71, 599-620.

79. Kane, B.E., Svensson, B., Ferguson, D.M. (2006) Molecular recognition of opioid receptor ligands. AAPS J. 8 , E126 - E137 .

80. Nowak, M., Kolaczkowski, M., Pawlowski, M., Bojarski, A.J. (2006) Homology modeling of the serotonin 5-HT1A receptor using automated docking of bioactive compounds with defined geometry. J Med Chem. 49, 205-214.

81. Okuno, Y., Tamon, A., Yabuuchi, H., Niijima, S., Minowa, Y., Tonomura, K., Kunimoto, R., Feng, C. (2008) GLIDA: GPCR ligand database for chemical genomics drug discovery database and tools update. Nucleic Acids Res. 36, D907-D912.

82. Roth , B.L. , Kroeze, W.K. , Patel , S. , Lopez , E. ( 2000 ) The multiplicity of serotonin receptors: Uselessly diverse molecules or an embarrassment of riches? Neuroscientist. 6 , 252 - 262 .

83. Wishart, D.S., Knox, C., Guo, A.C., Cheng, D., Shrivastava, S., Tzur, D., Gautam,

B., Hassanali, M. (2008) DrugBank: A knowledgebase for drugs, drug actions and drug targets. Nucleic Acids Res. 36, D901-D906.

84. Chen, J.Z., Wang, J., Xie, X.Q. (2007) GPCR structure-based virtual screening approach for CB2 antagonist search. J Chem Inf Model. 47,1626-1637.

85. Evers, A., Klabunde,T. (2005) Structure-based drug discovery using GPCR homol-ogy modeling: Successful virtual screening for antagonists of the alpha1A adren-ergic receptor. J Med Chem. 48,1088-1097.

86. Evers, A., Klebe, G. (2004) Successful virtual screening for a submicromolar antagonist of the neurokinin-1 receptor based on a ligand-supported homology model. J Med Chem. 47, 5381-5392.

87. Varady, J., Wu, X., Fang, X., Min, J., Hu, Z., Levant, B., Wang, S. (2003) Molecular modeling of the three-dimensional structure of dopamine 3 (D3) subtype receptor: Discovery of novel and potent D3 ligands through a hybrid pharmacophore-and structure-based database searching approach. J Med Chem. 46 , 4377 - 4392 .

88. Jacoby, E., Bouhelal, R., Gerspacher, M., Seuwen, K. (2006) The 7 TM G-protein-coupled receptor target family. ChemMedChem. 1, 761-782.

89. Emorine, L., Marullo, S., Briend-Sutren, M., Patey, G.,Tate, K., Delavier-Klutchko, C., Strosberg, A. (1989) Molecular characterization of the human p3-adrenergic receptor. Science. 245,1118-1121.

90. Kikkawa , H. , Kurose, H. , Isogaya , M. , Sato, Y. , Nagao, T. ( 1997 ) Differential contribution of two serine residues of wild type and constitutively active p 2-adrenoceptors to the interaction with beta2-selective agonists. Br J Pharmacol. 121,1059-1064.

91. Kikkawa, H., Isogaya, M., Nagao, T., Kurose, H. (1998) The role of the seventh transmembrane region in high affinity binding of a beta 2-selective agonist TA-2005. Mol Pharmacol. 53,128-134.

92. Cacciari, B., Bolcato, C., Spalluto, G., Klotz, K., Bacilieri, M., Deflorian, F., Moro, S. (2007) Pyrazolo-triazolo-pyrimidines as adenosine receptor antagonists: A complete structure-activity profile. Purinergic Signal. 3,183-193.

93. Jacobson, K.A., Gao, Z.-G. (2006) Adenosine receptors as therapeutic targets. Nat Rev Drug Discov. 5 , 247 - 264 .

94. Hoffmann, C., Zurn, A., Bunemann, M., Lohse, M.J. (2008) Conformational changes in G-protein-coupled receptors—The quest for functionally selective conformations is open. Br J Pharmacol. 153, S358-S366.

95. Kenakin,T. (2003) Ligand-selective receptor conformations revisited:The promise and the problem. Trends Pharmacol Sci. 24 , 346 - 354 .

96. Schwartz , T.W. , Frimurer, T.M. , Holst , B. , Rosenkilde, M.M. , Elling, C.E. ( 2006 ) Molecular mechanism of 7TM receptor activation—A global toggle switch model. Annu Rev Pharmacol Toxicol. 46,481-519.

97. Kobilka, B.K., Deupi, X. (2007) Conformational complexity of G-protein-coupled receptors. Trends Pharmacol Sci. 28, 397-406.

98. Scheerer, P. , Park , J.H. , Hildebrand , P.W. , Kim , Y.J. , Krausz , N. , Choe, H. - W., Hofmann, K.P., Ernst, O.P. (2008) Crystal structure of opsin in its G-protein-interacting conformation . Nature. 455 , 497 - 502 .

99. Shi , L. , Liapakis, G. , Xu , R. , Guarnieri , F. , Ballesteros, J.A. , Javitch , J.A. ( 2002 ) Beta2 adrenergic receptor activation. Modulation of the proline kink in transmembrane 6 by a rotamer toggle switch. J Biol Chem. 277 , 40989 - 40996 .

100. McAllister, S.D., Hurst, D.P., Barnett-Norris, J., Lynch, D., Reggio, P.H., Abood, M.E. (2004) Structural mimicry in class A G protein-coupled receptor rotamer toggle switches: The importance of the F3.36(201)/W6.48(357) interaction in can-nabinoid CB1 receptor activation. J Biol Chem. 279,48024-48037.

101. Crocker, E., Eilers, M., Ahuja, S., Hornak, V., Hirshfeld, A., Sheves, M., Smith, S.O. (2006) Location of Trp265 in metarhodopsin II: Implications for the activation mechanism of the visual receptor rhodopsin. J Mol Biol. 357 , 163 - 72 .

102. Fanelli,F.,De Benedetti,P.G. (2006) Inactive and active states and supramolecular organization of GPCRs: Insights from computational modeling. J Comput Aided Mol Des. 20,449-461.

103. Angelova, K., Fanelli, F., Puett, D. (2008) Contributions of intracellular loops 2 and 3 of the lutropin receptor in Gs coupling. Mol Endocrinol. 22,126-138.

104. Raimondi, F., Seeber, M., Benedetti, P.G., Fanelli, F. (2008) Mechanisms of inter-and intramolecular communication in GPCRs and G proteins . J Am Chem Soc. 130,4310-4325.

105. Filipek, S., Krzysko, K.A., Fotiadis, D., Liang, Y., Saperstein, D.A., Engel, A., Palczewski, K. (2004) A concept for G protein activation by G protein-coupled receptor dimers: The transducin/rhodopsin interface. Photochem Photobiol Sci. 3, 628 - 638 .

106. Sexton, P.M., Morfis, M., Tilakaratne, N., Hay, D.L., Udawela, M., Christopoulos, G., Christopoulos, A. (2006) Complexing receptor pharmacology: Modulation of family B G protein-coupled receptor function by RAMPs. Ann N Y Acad Sci. 1070, 90 - 104 .

107. Milligan, G. (2008) A day in the life of a G protein-coupled receptor: The contribution to function of G protein-coupled receptor dimerization . Br J Pharmacol. 153 , S216 - S229 .

108. Whorton, M.R., Jastrzebska, B., Park, P.S., Fotiadis, D., Engel, A., Palczewski, K., Sunahara, R.K. (2008) Efficient coupling of transducin to monomeric rhodopsin in a phospholipid bilayer. J Biol Chem. 283 , 4387 - 4394 .

109. Gurevich, V.V., Gurevich, E.V. (2008) GPCR monomers and oligomers: It takes all kinds. Trends Neurosci. 31, 74-81.

110. Fotiadis, D., Liang, Y., Filipek, S., Saperstein, D.A., Engel, A., Palczewski, K. (2003) Atomic-force microscopy: Rhodopsin dimers in native disc membranes. Nature. 421,127-128.

111. Fotiadis, D., Liang, Y., Filipek, S., Saperstein, D.A., Engel, A., Palczewski, K. (2004) The G protein-coupled receptor rhodopsin in the native membrane. FEBS Lett. 564 , 281 - 288 .

112. Milligan , G. , Canals, M. , Pediani , J.D. , Ellis, J. , Lopez - Gimenez , J.F. ( 2006 ) The role of GPCR dimerisation/oligomerisation in receptor signalling. Ernst Schering Found Symp Proc. 2,145-161.

113. Casado,V., Cortes,A., Ciruela, F., Mallol, J., Ferre, S., Lluis, C., Canela, E.I., Franco, R. (2007) Old and new ways to calculate the affinity of agonists and antagonists interacting with G-protein-coupled monomeric and dimeric receptors: The recep-tor-dimer cooperativity index. Pharmacol Ther. 116, 343-354.

114. Franco, R., Casado, V., Cortes, A., Mallol, J., Ciruela, F., Ferre, S., Lluis, C., Canela, E.I. (2008) G-protein-coupled receptor heteromers: Function and ligand pharmacology. Br J Pharmacol. 153, S90-S98.

115. Harikumar, K.G. , Morfis, M.M. , Sexton , P.M. , Miller, L.J. ( 2008 ) Pattern of intra -family hetero - oligomerization involving the G - protein - coupled secretin receptor. J Mol Neurosci. 36, 279-285.

116. Fanelli, F. (2007) Dimerization of the lutropin receptor: Insights from computational modeling. Mol Cell Endocrinol. 260-262, 59-64.

117. Casciari, D., Seeber, M., Fanelli, F. (2006) Quaternary structure predictions of transmembrane proteins starting from the monomer: A docking-based approach. BMC Bioinformatics. 7, 340.

118. Fanelli,F., Dell'orco, D. (2008) Dark and photoactivated rhodopsin share common binding modes to transducin . FEBS Lett. 582, 991-996.

119. Puett, D., Li, Y., DeMars, G., Angelova, K., Fanelli, F. (2007) A functional transmembrane complex: The luteinizing hormone receptor with bound ligand and G protein. Mol Cell Endocrinol. 260-262,126-136.

120. Kovacs, J.A., Baker, K.A., Altenberg, G.A., Abagyan, R., Yeager, M. (2007) Molecular modeling and mutagenesis of gap junction channels. Prog Biophys Mol Biol. 94,15-28.

121. Kovacs, J.A., Yeager, M., Abagyan, R. (2007) Computational prediction of atomic structures of helical membrane proteins aided by EM maps. Biophys J. 93, 1950 - 1959 .

122. Tyndall, J., Sandilya, R. (2005) GPCR agonists and antagonists in the clinic. Med Chem. 1, 405-421.

123. Lagerstrom, M.C., Schioth, H.B. (2008) Structural diversity of G protein-coupled receptors and significance for drug discovery. Nat Rev Drug Discov. 7, 339-357.

124. Soudijn, W., Van Wijngaarden, I., Ap, I.J. (2004) Allosteric modulation of G protein-coupled receptors: Perspectives and recent developments. Drug Discov Today. 9, 752-758.

125. Langmead, C.J., Christopoulos, A. (2006) Allosteric agonists of 7TM receptors: Expanding the pharmacological toolbox. Trends Pharmacol Sci. 27,475-481.

126. Raddatz , R. , Schaffhauser, H. , Marino, M.J. ( 2007 ) Allosteric approaches to the targeting of G-protein-coupled receptors for novel drug discovery: A critical assessment. Biochem Pharmacol. 74, 383-391.

127. Grace, C.R., Perrin, M.H., DiGruccio, M.R., Miller, C.L., Rivier, J.E., Vale, W.W., Riek. R. (2004) NMR structure and peptide hormone binding site of the first extracellular domain of a type B1 G protein-coupled receptor. Proc Natl Acad Sci U S A. 101,12836-12841.

128. Parthier, C. , Kleinschmidt , M. , Neumann , P. , Rudolph , R. , Manhart , S. , Schlenzig, D., Fanghanel, J., Rahfeld, J.U., Demuth, H.U., Stubbs, M.T. (2007) Crystal structure of the incretin-bound extracellular domain of a G protein-coupled receptor. Proc Natl Acad Sci U S A. 104,13942-13947.

129. Pioszak, A.A., Xu, H.E. (2008) Molecular recognition of parathyroid hormone by its G protein-coupled receptor. Proc Natl Acad Sci U S A. 105, 5034-5039.

130. Dong, M., Ding, X.Q., Thomas, S.E., Gao, F., Lam, P.C., Abagyan, R., Miller, L.J. (2007) Role of lysine187 within the second extracellular loop of the type A cho-lecystokinin receptor in agonist-induced activation. Use of complementary charge-reversal mutagenesis to define a functionally important interdomain interaction. Biochemistry. 46,4522-4531.

131. Dong, M. , Lam , P.C. , Pinon , D.I. , Sexton , P.M. , Abagyan , R. , Miller, L.J. ( 2008 ) Spatial approximation between secretin residue five and the third extracellular loop of its receptor provides new insight into the molecular basis of natural agonist binding. Mol Pharmacol. 74,413-422.

132. Harikumar, K.G., Lam, P.C., Dong, M., Sexton, P.M., Abagyan, R., Miller, L.J. (2007) Fluorescence resonance energy transfer analysis of secretin docking to its receptor: Mapping distances between residues distributed throughout the ligand pharmacophore and distinct receptor residues. J Biol Chem. 282, 32834-32843.

133. Dong, M., Lam, P.C., Gao, F., Hosohata, K., Pinon, D.I., Sexton, P.M., Abagyan, R., Miller, L.J. (2007) Molecular approximations between residues 21 and 23 of secretin and its receptor: Development of a model for peptide docking with the amino terminus of the secretin receptor. Mol Pharmacol. 72, 280-290.

134. Chen, C., Dagnino Jr., R., De Souza, E.B., Grigoriadis, D.E., Huang, C.Q., Kim, K.I., Liu, Z., Moran, T., Webb, T.R., Whitten, J.P., Xie, Y.F., McCarthy, J.R. (1996) Design and synthesis of a series of non-peptide high-affinity human corticotropin-releasing factor1 receptor antagonists. J Med Chem. 39 , 4358 - 4360 .

135. Chen , C. , Dagnino Jr. , R. , Huang, C.Q. , McCarthy, J.R. , Grigoriadis, D.E. ( 2001 ) 1-Alkyl-3-amino-5-aryl-1H-[1, 2, 4]triazoles: Novel synthesis via cyclization of N - acyl - S - methylisothioureas with alkylhydrazines and their potent corticotropin -releasing factor-1 (CRF(1)) receptor antagonist activities. Bioorg Med Chem Lett. 11 , 3165 - 3168 .

136. Chen, C., Wilcoxen, K.M., Huang, C.Q., McCarthy, J.R., Chen,T., Grigoriadis, D.E.

(2004) Optimization of 3-phenylpyrazolo[1, 5-a]pyrimidines as potent corticotro-pin-releasing factor-1 antagonists with adequate lipophilicity and water solubility. Bioorg Med Chem Lett. 14, 3669-3673.

137. Hoare, S.R., Fleck, B.A., Gross, R.S., Crowe, P.D., Williams, J.P., Grigoriadis, D.E. (2008) Allosteric ligands for the corticotropin releasing factor type 1 receptor modulate conformational states involved in receptor activation. Mol Pharmacol. 73 , 1371 - 1380 .

138. Huang, C.Q. , Wilcoxen , K.M. , Grigoriadis, D.E. , McCarthy, J.R. , Chen , C. ( 2004 ) Design and synthesis of 3-(2-pyridyl)pyrazolo[1, 5-a]pyrimidines as potent CRF1 receptor antagonists. Bioorg Med Chem Lett. 14, 3943-3947.

139. St-Denis, Y., Di Fabio, R., Bernasconi, G., Castiglioni, E., Contini, S., Donati, D., Fazzolari, E., Gentile, G., Ghirlanda, D., Marchionni, C., Messina, F., Micheli, F., Pavone, F., Pasquarello, A., Sabbatini, F.M., Zampori, M.G., Arban, R., Vitulli, G.

(2005) Substituted tetraazaacenaphthylenes as potent CRF1 receptor antagonists for the treatment of depression and anxiety. Bioorg Med Chem Lett. 15 , 3713-3716.

140. Ising, M. , Zimmermann , U.S. , Kunzel , H.E. , Uhr, M. , Foster, A.C. , Learned -Coughlin, S.M., Holsboer, F., Grigoriadis, D.E. (2007) High-affinity CRF1 receptor antagonist NBI-34041: Preclinical and clinical data suggest safety and efficacy in attenuating elevated stress response. Neuropsychopharmacology. 32,1941-1949.

141. Bjarnadottir, T.K., Fredriksson, R., Schioth, H.B. (2005) The gene repertoire and the common evolutionary history of glutamate, pheromone (V2R), taste(1) and other related G protein-coupled receptors. Gene. 362, 70 - 84 .

142. Gasparini, F., Kuhn, R., Pin, J.P. (2002) Allosteric modulators of group I metabo-tropic glutamate receptors: Novel subtype-selective ligands and therapeutic perspectives. Curr Opin Pharmacol. 2 , 43 - 49 .

143. Lavreysen, H., Dautzenberg, F.M. (2008) Therapeutic potential of group III metabotropic glutamate receptors. Curr Med Chem. 15, 671-684.

144. Recasens, M., Guiramand, J., Aimar, R., Abdulkarim, A., Barbanel, G. (2007) Metabotropic glutamate receptors as drug targets. Curr Drug Targets. 8, 651-681.

145. Shoback , D.M. , Bilezikian , J.P. , Turner, S.A. , McCary, L.C. , Guo, M.D. , Peacock , M. (2003) The calcimimetic cinacalcet normalizes serum calcium in subjects with primary hyperparathyroidism . J Clin Endocrinol Metab. 88, 5644-5649.

146. Kunishima, N., Shimada, Y., Tsuji, Y., Sato, T., Yamamoto, M., Kumasaka, T., Nakanishi, S., Jingami, H., Morikawa, K. (2000) Structural basis of glutamate recognition by a dimeric metabotropic glutamate receptor. Nature. 407, 971-977.

147. Tsuchiya, D., Kunishima, N., Kamiya, N., Jingami, H., Morikawa, K. (2002) Structural views of the ligand-binding cores of a metabotropic glutamate receptor complexed with an antagonist and both glutamate and Gd3+. Proc Natl Acad Sci U S A. 99, 2660-2665.

148. Muto,T.,Tsuchiya, D., Morikawa, K., Jingami, H. (2007) Structures of the extracellular regions of the group II/III metabotropic glutamate receptors. Proc Natl Acad Sci U S A. 104, 3759-3764.

149. Belenikin, M.S., Baskin, I.I., Costantino, G., Palyulin, V.A., Pellicciari, R., Zefirov, N.S. (2002) Comparative analysis of the ligand-binding sites of the metabotropic glutamate receptors mGluR1-mGluR8. Dokl Biochem Biophys. 386, 251-256.

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

151. Wang, M. , Yao, Y. , Kuang, D. , Hampson , D.R. ( 2006 ) Activation of family C G-protein-coupled receptors by the tripeptide glutathione. J Biol Chem. 281, 8864 - 8870 .

152. Pellicciari, R., Filosa, R., Fulco, M.C., Marinozzi, M., Macchiarulo, A., Novak, C., Natalini, B., Hermit, M.B., Nielsen, S., Sager, T.N., Stensbol, T.B., Thomsen, C. (2006) Synthesis and preliminary biological evaluation of 2' -substituted 2-(3'-car-boxybicyclo[1.1.1]pentyl)glycine derivatives as group I selective metabotropic glutamate receptor ligands. ChemMedChem. 1 , 358 - 365 .

153. Pellicciari, R., Marinozzi, M., Macchiarulo,A., Fulco, M.C., Gafarova, J., Serpi, M., Giorgi, G., Nielsen, S., Thomsen, C. (2007) Synthesis, molecular modeling studies, and preliminary pharmacological characterization of all possible 2-(2' -sulfonocy-clopropyl)glycine stereoisomers as conformationally constrained L-homocysteic acid analogs. J Med Chem. 50, 4630-4641.

154. Lavreysen, H., Janssen, C., Bischoff, F., Langlois, X., Leysen, J.E., Lesage, A.S. ( 2003 ) [3H]R214127: A novel high - affinity radioligand for the mGlu1 receptor reveals a common binding site shared by multiple allosteric antagonists. Mol Pharmacol. 63,1082-1093.

155. Malherbe, P., Kratochwil, N., Zenner, M.T., Piussi, J., Diener, C., Kratzeisen, C., Fischer, C., Porter, R.H. (2003) Mutational analysis and molecular modeling of the binding pocket of the metabotropic glutamate 5 receptor negative modulator 2-methyl-6-(phenylethynyl)-pyridine. Mol Pharmacol. 64, 823-832.

156. Malherbe, P., Kratochwil, N., Muhlemann, A., Zenner, M.T., Fischer, C., Stahl, M., Gerber, P.R., Jaeschke, G., Porter, R.H. (2006) Comparison of the binding pockets of two chemically unrelated allosteric antagonists of the mGlu5 receptor and identification of crucial residues involved in the inverse agonism of MPEP. J Neurochem. 98 , 601 - 615 .

157. Muhlemann, A., Ward, N.A., Kratochwil, N., Diener, C., Fischer, C., Stucki, A., Jaeschke, G., Malherbe, P., Porter, R.H. (2006) Determination of key amino acids implicated in the actions of allosteric modulation by 3,3'-difluorobenzaldazine on rat mGlu5 receptors. Eur J Pharmacol. 529 , 95 - 104 .

158. Ray, K.,Tisdale, J., Dodd,R.H., Dauban, P.,Ruat, M.,Northup, J.K. (2005) Calindol, a positive allosteric modulator of the human Ca(2+) receptor, activates an extra cellular ligand - binding domain - deleted rhodopsin - like seven - transmembrane structure in the absence of Ca(2+). J Biol Chem. 280, 37013-37020.

159. Kratochwil, N.A., Malherbe, P., Lindemann, L., Ebeling, M., Hoener, M.C., Muhlemann, A., Porter, R.H., Stahl, M., Gerber, P.R. (2005) An automated system for the analysis of G protein-coupled receptor transmembrane binding pockets: Alignment, receptor-based pharmacophores, and their application . J Chem Inf Model. 45,1324-1336.

160. Noeske,T., Jirgensons, A., Starchenkovs, I., Renner, S., Jaunzeme, I.,Trifanova, D., Hechenberger, M., Bauer,T., Kauss, V., Parsons, C.G., Schneider, G.,Weil,T. (2007) Virtual screening for selective allosteric mGluR1 antagonists and structure-activity relationship investigations for coumarine derivatives. ChemMedChem. 2, 1763 - 1773 .

161. Radestock, S., Weil, T., Renner, S. (2008) Homology model-based virtual screening for GPCR ligands using docking and target-biased scoring. J Chem Inf Model. 48, 1104-1117.

162. Yanamala,N.,Tirupula, K.C.,Klein-Seetharaman, J. (2008) Preferential binding of allosteric modulators to active and inactive conformational states of metabotropic glutamate receptors. BMC Bioinformatics. 9 , S16 .

163. Jacoby, E., Schuffenhauer, A., Floersheim, P. (2003) Chemogenomics knowledge-based strategies in drug discovery. Drug News Perspect. 16, 93-102.

164. Bock, J.R., Gough, D.A. (2005) Virtual screen for ligands of orphan G proteincoupled receptors. J Chem InfModel. 45,1402-1414.

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