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G protein-coupled receptors: the evolution of structural insight

Department of Chemistry, University of Memphis, 3744 Walker Ave, Memphis, TN 38152, USA

G protein-coupled receptors (GPCR) comprise a diverse superfamily of over 800 proteins that have gained relevance as biological targets for pharmaceutical drug design. Although these receptors have been investigated for decades, three-dimensional structures of GPCR have only recently become available. In this review, we focus on the technological advancements that have facilitated efforts to gain insights into GPCR structure. Progress in these efforts began with the initial crystal structure determination of rhodopsin (PDB: 1F88) in 2000 and has continued to the most recently published structure of the A1AR (PDB: 5UEN) in 2017. Numerous experimental developments over the past two decades have opened the door for widespread GPCR structural characterization. These efforts have resulted in the determination of three-dimensional structures for over 40 individual GPCR family members. Herein we present a comprehensive list and comparative analysis of over 180 individual GPCR structures. This includes a summary of different GPCR functional states crystallized with agonists, dual agonists, partial agonists, inverse agonists, antagonists, and allosteric modulators.
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1. Venter JC, Adams MD, Myers EW, et al. (2001) The sequence of the human genome. Science 291: 1304–1351.    

2. Lander ES, Linton LM, Birren B, et al. (2001) Initial sequencing and analysis of the human genome. Nature 409: 860–921.    

3. Fredriksson R, Lagerstrom MC, Lundin LG, et al. (2003) The G-protein-coupled receptors in the human genome form five main families. Phylogenetic analysis, paralogon groups, and fingerprints. Mol Pharmacol 63: 1256–1272.

4. Pierce KL, Premont RT, Lefkowitz RJ (2002) Seven-transmembrane receptors. Nat Rev Mol Cell Biol 3: 639–650.    

5. Lagerstrom MC, Schioth HB (2008) Structural diversity of G protein-coupled receptors and significance for drug discovery. Nat Rev Drug Discov 7: 339–357.    

6. Chien EY, Liu W, Zhao Q, et al. (2010) Structure of the human dopamine D3 receptor in complex with a D2/D3 selective antagonist. Science 330: 1091–1095.    

7. Yang J, Villar VA, Armando I, et al. (2016) G protein-coupled receptor kinases: Crucial regulators of blood pressure. J Am Heart Assoc 5: e003519.    

8. Bar-Shavit R, Maoz M, Kancharla A, et al. (2016) G protein-coupled receptors in cancer. Int J Mol Sci 17: 1320.    

9. Flower DR (1999) Modelling G-protein-coupled receptors for drug design. Biochim Biophys Acta 1422: 207–234.    

10. Katritch V, Cherezov V, Stevens RC (2012) Diversity and modularity of G protein-coupled receptor structures. Trends Pharmacol Sci 33: 17–27.    

11. Gether U, Ballesteros JA, Seifert R, et al. (1997) Structural instability of a constitutively active G protein-coupled receptor. Agonist-independent activation due to conformational flexibility. J Biol Chem 272: 2587–2590.

12. Seifert R, 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.    

13. Nelson G, Hoon MA, Chandrashekar J, et al. (2001) Mammalian sweet taste receptors. Cell 106: 381–390.    

14. Nelson G, Chandrashekar J, Hoon MA, et al. (2002) An amino-acid taste receptor. Nature 416: 199–202.    

15. Milligan G (2004) G protein-coupled receptor dimerization: Function and ligand pharmacology. Mol Pharmacol 66.

16. Syrovatkina V, Alegre KO, Dey R, et al. (2016) Regulation, signaling, and physiological functions of G-proteins. J Mol Biol 428: 3850–3868.    

17. Wess J (1997) G-protein-coupled receptors: molecular mechanisms involved in receptor activation and selectivity of G-protein recognition. FASEB J 11: 346–354.

18. Rasumussen SG, DeVree BT, Zou Y, et al. (2011) Crystal structure of the beta2 adrenergic receptor-Gs protein complex. Nature 477: 549–555.    

19. Gilman AG (1987) G proteins: transducers of receptor-generated signals. Annu Rev Biochem 56: 615–649.    

20. Nie J, Lewis DL (2001) Structural domains of the CB1 cannabinoid receptor that contribute to constitutive activity and G-protein sequestration. J Neurosci 21: 8758–8764.

21. Kobilka BK, Deupi X (2007) Conformational complexity of G-protein-coupled receptors. Trends Pharmacol Sci 28: 397–406.    

22. Ross EM, Wilkie TM (2000) GTPase-activating proteins for heterotrimeric G proteins: regulators of G protein signaling (RGS) and RGS-like proteins. Annu Rev Biochem 69: 795–827.    

23. Claing A, Laporte SA, Caron MG, et al. (2002) Endocytosis of G protein-coupled receptors: roles of G protein-coupled receptor kinases and beta-arrestin proteins. Prog Neurobiol 66: 61–79.    

24. Okada T, Le TI, Fox BA, et al. (2000) X-Ray diffraction analysis of three-dimensional crystals of bovine rhodopsin obtained from mixed micelles. J Struct Biol 130: 73–80.    

25. Palczewski K, Kumasaka T, Hori T, et al. (2000) Crystal structure of rhodopsin: A G protein-coupled receptor. Science 289: 739–745.    

26. Cherezov V, Rosenbaum DM, Hanson MA, et al. (2007) High resolution crystal structure of an engineered human beta2-adrenergic G protein-couple receptor. Science 318: 1258–1265.    

27. Rasmussen SG, Choi HJ, Rosenbaum DM, et al. (2007) Crystal structure of the human beta2 adrenergic G-protein-coupled receptor. Nature 450: 383–387.    

28. Stroud RM (2011) New tools in membrane protein determination. F1000 Biol Rep 3: 8.

29. Ujwal R, Bowie JU (2011) Crystallizing membrane proteins using lipidic bicelles. Methods 55: 337–341.    

30. Denisov IG, Sligar SG (2016) Nanodiscs for structural and functional studies of membrane proteins. Nat Struct Mol Biol 23: 481–486.    

31. Xiang J, Chun E, Liu C, et al. (2016) Successful strategies to determine high-resolution structures of GPCRs. Trends Pharmacol Sci 37: 1055–1069.    

32. Rawlings AE (2016) Membrane proteins: always an insoluble problem? Biochem Soc Trans 44: 790–795.    

33. Neubig RR, Siderovski DP (2002) Regulators of G-protein signalling as new central nervous system drug targets. Nat Rev Drug Discov 1: 187–197.    

34. Bayburt TH, Grinkova YV, Sligar SG (2002) Self-assembly of discoidal phospholipid bilayer nanoparticles with membrane scaffold proteins. Nano Lett 2: 853–856.    

35. Delmar JA, Bolla JR, Su CC, et al. (2015) Crystallization of membrane proteins by vapor diffusion. Methods Enzymol 557: 363–392.    

36. Jaakola VP, Griffith MT, Hanson MA, et al. (2008) The 2.6 angstrom crystal structure of a human A2A adenosine receptor bound to an antagonist. Science 322: 1211–1217.

37. Dore AS, Okrasa K, Patel JC, et al. (2014) Structure of class C GPCR metabotropic glutamate receptor 5 transmembrane domain. Nature 511: 557–562.    

38. Thompson AA, Liu W, Chun E, et al. (2012) Structure of the nociceptin/orphanin FQ receptor in complex with a peptide mimetic. Nature 485: 395–399.    

39. Wang C, Wu H, Katritch V, et al. (2013) Structure of the human smoothened receptor bound to an antitumour agent. Nature 497: 338–343.    

40. Yin J, Babaoglu K, Brautigam CA, et al. (2016) Structure and ligand-binding mechanism of the human OX1 and OX2 orexin receptors. Nat Struct Mol Biol 23: 293–299.    

41. Zhang K, Zhang J, Gao Z, et al. (2014) Structure of the human P2Y12 receptor in complex with an antithrombotic drug. Nature 509.

42. Isberg V, Mordalski S, Munk C, et al. (2016) GPCRdb: an information system for G protein-coupled receptors. Nucleic Acids Res.

43. Berman HM, Westbrook J, Feng Z, et al. (2000) The protein data bank. Nucl Acids Res 28: 235–242.    

44. Teller DC, Okada T, Behnke CA, et al. (2001) Advances in determination of a high-resolution three-dimensional structure of rhodopsin, a model of G-protein-coupled receptors (GPCRs). Biochemistry 40: 7761–7772.    

45. Yeagle PL, Choi G, Albert AD (2001) Studies on the structure of the G-protein-coupled receptor rhodopsin including the putative G-protein binding site in unactivated and activated forms. Biochemistry 40: 11932–11937.    

46. Okada T, Fujiyoshi Y, Silow M, et al. (2002) Functional role of internal water molecules in rhodopsin revealed by X-ray crystallography. Proc Natl Acad Sci USA 99: 5982–5987.    

47. Choi G, Landin J, Galan JF, et al. (2002) Structural studies of metarhodopsin II, the activated form of the G-protein coupled receptor, rhodopsin. Biochemistry 41: 7318–7324.    

48. Li J, Edwards PC, Burghammer M, et al. (2004) Structure of bovine rhodopsin in a trigonal crystal form. J Mol Biol 343: 1409–1438.    

49. Okada T, Sugihara M, Bondar AN, et al. (2004) The retinal conformation and its environment in rhodopsin in light of a new 22 A crystal structure. J Mol Biol 342: 571–583.    

50. Nakamichi H, Okada T (2006) Crystallographic analysis of primary visual photochemistry. Angew Chem Int Ed Engl 45: 4270–4273.    

51. Nakamichi H, Okada T (2006) Local peptide movement in the photoreaction intermediate of rhodopsin. Proc Natl Acad Sci USA 103: 12729–12734.    

52. Salom D, Lodowski DT, Stenkamp RE, et al. (2006) Crystal structure of a photoactivated deprotonated intermediate of rhodopsin. Proc Natl Acad Sci USA 103: 16123–16128.    

53. Standfuss J, Xie G, Edwards PC, et al. (2007) Crystal structure of a thermally stable rhodopsin mutant. J Mol Biol 372: 1179–1188.    

54. Nakamichi H, Buss V, Okada T (2007) Photoisomerization mechanism of rhodopsin and 9-cis-rhodopsin revealed by x-ray crystallography. Biophys J 92: L106–L108.    

55. Stenkamp RE (2008) Alternative models for two crystal structures of bovine rhodopsin. Acta Crystallogr D D64: 902–904.

56. Park JH, Scheerer P, Hofmann KP, et al. (2008) Crystal structure of the ligand-free G-protein-coupled receptor opsin. Nature 454: 183–187.    

57. Scheerer P, Park JH, Hildebrand PW, et al. (2008) Crystal structure of opsin in its G-protein-interacting conformation. Nature 455: 497–502.    

58. Standfuss J, Edwards PC, D'Antona A, et al. (2011) The structural basis of agonist-induced activation in constitutively active rhodopsin. Nature 471: 656–660.    

59. Makino CL, Riley CK, Looney J, et al. (2010) Binding of more than one retinoid to visual opsins. Biophys J 99: 2366–2373.    

60. Choe HW, Kim YJ, Park JH, et al. (2011) Crystal structure of metarhodopsin II. Nature 471: 651–655.    

61. Deupi X, Edwards P, Singhal A, et al. (2012) Stabilized G protein binding site in the structure of constitutively active metarhodopsin-II. Proc Natl Acad Sci USA 109: 119–124.    

62. Park JH, Morizumi T, Li Y, et al. (2013) Opsin, a structural model for olfactory receptors? Angew Chem Int Ed Engl 52: 11021–11024.    

63. Singhal A, Ostermaier MK, Vishnivetskiy SA, et al. (2013) Insights into congenital stationary night blindness based on the structure of G90D rhodopsin. EMBO Rep 14: 520–526.    

64. Szczepek M, Beyriere F, Hofmann KP, et al. (2014) Crystal structure of a common GPCR-binding interface for G protein and arrestin. Nat Commun 5: 4801.    

65. Blankenship E, Vahedi-Faridi A, Lodowski DT (2015) The high-resolution structure of activated opsin reveals a conserved solvent network in the transmembrane region essential for activation. Structure 23: 2358–2364.    

66. Kang Y, Zhou XE, Gao X, et al. (2015) Crystal structure of rhodopsin bound to arrestin by femtosecond X-ray laser. Nature 523: 561–567.    

67. Singhal A, Guo Y, Matkovic M, et al. (2016) Structural role of the T94I rhodopsin mutation in congenital stationary night blindness. EMBO Rep 17: 1431–1440.    

68. Gulati S, Jastrzebska B, Banerjee S, et al. (2017) Photocyclic behavior of rhodopsin induced by an atypical isomerization mechanism. Proc Natl Acad Sci USA 114: E2608–E2615.    

69. Warne T, Serrano-Vega MJ, Baker JG, et al. (2008) Structure of a beta1-adrenergic G-protein-coupled receptor. Nature 454: 486–491.    

70. Warne T, Moukhametzianov R, Baker JG, et al. (2011) The structural basis for agonist and partial agonist action on a beta(1)-adrenergic receptor. Nature 469: 241–244.    

71. Moukhametzianov R, Warne T, Edwards PC, et al. (2011) Two distinct conformations of helix 6 observed in antagonist-bound structures of a beta-1 adrenergic receptor. Proc Natl Acad Sci USA 108: 8228–8232.    

72. Christopher JA, Brown J, Dore AS, et al. (2013) Biophysical fragment screening of the beta1-adrenergic receptor: identification of high affinity arylpiperazine leads using structure-based drug design. J Med Chem 56: 3446–3455.    

73. Warne T, Edwards PC, Leslie AG, et al. (2012) Crystal structures of a stabilized beta1-adrenoceptor bound to the biased agonists bucindolol and carvedilol. Structure 20: 841–849.    

74. Miller-Gallacher JL, Nehme R, Warne T, et al. (2014) The 2.1 A resolution structure of cyanopindolol-bound beta1-adrenoceptor identifies an intramembrane Na+ ion that stabilises the ligand-free receptor. PLoS One 9: e92727.

75. Huang J, Chen S, Zhang JJ, et al. (2013) Crystal structure of oligomeric beta1-adrenergic G protein-coupled receptors in ligand-free basal state. Nat Struct Mol Biol 20: 419–425.    

76. Sato T, Baker J, Warne T, et al. (2015) Pharmacological analysis and structure determination of 7-Methylcyanopindolol-bound beta1-adrenergic receptor. Mol Pharmacol 88: 1024–1034.    

77. Leslie AG, Warne T, Tate CG (2015) Ligand occupancy in crystal structure of beta1-adrenergic G protein-coupled receptor. Nat Struct Mol Biol 22: 941–942.    

78. Hanson MA, Cherezov V, Griffith MT, et al. (2008) A specific cholesterol binding site is established by the 2.8 A structure of the human beta2-adrenergic receptor. Structure 6: 897–905.

79. Bokoch MP, Zou Y, Rasmussen SG, et al. (2010) Ligand-specific regulation of the extracellular surface of a G-protein-coupled receptor. Nature 463: 108–112.    

80. Wacker D, Fenalti G, Brown MA, et al. (2010) Conserved binding mode of human beta2 adrenergic receptor inverse agonists and antagonist revealed by X-ray crystallography. J Am Chem Soc 132: 11443–11445.    

81. Rasmussen SG, Choi HJ, Fung JJ, et al. (2011) Structure of a nanobody-stabilized active state of the beta(2) adrenoceptor. Nature 469: 175–180.    

82. Rosenbaum DM, Zhang C, Lyons JA, et al. (2011) Structure and function of an irreversible agonist-beta(2) adrenoceptor complex. Nature 469: 236–240.    

83. Zou Y, Weis WI, Kobilka BK (2012) N-terminal T4 lysozyme fusion facilitates crystallization of a G protein coupled receptor. PLos One 7.

84. Ring AM, Manglik A, Kruse AC, et al. (2013) Adrenaline-activated structure of beta2-adrenoreceptor stabilized by an engineered nanobody. Nature 502: 575–579.    

85. Weichert D, Kruse AC, Manglik A, et al. (2014) Covalent agonists for studying G protein-coupled receptor activation. Proc Natl Acad Sci USA 111: 10744–10748.    

86. Huang CY, Olieric V, Ma P, et al. (2016) In meso in situ serial X-ray crystallography of soluble and membrane proteins at cryogenic temperatures. Acta Crystallogr D 72: 93–112.    

87. Staus DP, Strachan RT, Manglik A, et al. (2016) Allosteric nanobodies reveal the dynamic range and diverse mechanisms of G-protein-coupled receptor activation. Nature 535: 448–452.    

88. Shimamura T, Shiroishi M, Weyand S, et al. (2011) Structure of the human histamine H1 receptor complex with doxepin. Nature 475: 65–70.    

89. Wang C, Jiang Y, Ma J, et al. (2013) Structural basis for molecular recognition at serotonin receptors. Science 340: 610–614.    

90. Wacker D, Wang C, Katritch V, et al. (2013) Structural features for functional selectivity at serotonin receptors. Science 340: 615–619.    

91. Liu W, Wacker D, Gati C, et al. (2013) Serial femtosecond crystallography of G protein-coupled receptors. Science 342: 1521–1524.    

92. Wacker D, Wang S, McCorvy JD, et al. (2017) Crystal structure of an LSD-bound human serotonin receptor. Cell 168: 377–389.    

93. Thal DM, Sun B, Feng D, et al. (2016) Crystal structures of the M1 and M4 muscarinic acetylcholine receptors. Nature 531: 335–340.    

94. Haga K, Kruse AC, Asada H, et al. (2012) Structure of the human M2 muscarinic acetylcholine receptor bound to an antagonist. Nature 482: 547–551.    

95. Kruse AC, Ring AM, Manglik A, et al. (2013) Activation and allosteric modulation of a muscarinic acetylcholine receptor. Nature 504: 101–106.    

96. Kruse AC, Hu J, Pan AC, et al. (2012) Structure and dynamics of the M3 muscarinic acetylcholine receptor. Nature 482: 552–556.    

97. Thorsen TS, Matt R, Weis WI, et al. (2014) Modified T4 lysozyme fusion proteins facilitate G protein-coupled receptor crystallogenesis. Structure 22: 1657–1664.    

98. Glukhova A, Thal DM, Nguyen AT, et al. (2017) Structure of the adenosine A1 receptor reveals the basis for subtype selectivity. Cell 168: 867–877.    

99. Dore AS, Robertson N, Errey JC, et al. (2011) Structure of the adenosine A(2A) receptor in complex with ZM241385 and the xanthines XAC and caffeine. Structure 19: 1283–1293.    

100. Xu F, Wu H, Katritch V, et al. (2011) Structure of an agonist-bound human A2A adenosine receptor. Science 332: 322–327.    

101. Lebon G, Warne T, Edwards PC, et al. (2011) Agonist-bound adenosine A2A receptor structures reveal common features of GPCR activation. Nature 474: 521–525.    

102. Hino T, Arakawa T, Iwanari H, et al. (2012) G-protein-coupled receptor inactivation by an allosteric inverse-agonist antibody. Nature 482: 237–240.

103. Congreve M, Andrews SP, Dore AS, et al. (2012) Discovery of 1,2,4-triazine derivatives as adenosine A(2A) antagonists using structure based drug design. J Med Chem 55: 1898–1903.    

104. Liu W, Chun E, Thompson AA, et al. (2012) Structural basis for allosteric regulation of GPCRs by sodium ions. Science 337: 232–236.    

105. Lebon G, Edwards PC, Leslie AG, et al. (2015) Molecular determinants of CGS21680 binding to the human adenosine A2A receptor. Mol Pharmacol 87: 907–915.    

106. Segala E, Guo D, Cheng RK, et al. (2016) Controlling the dissociation of ligands from the adenosine A2A receptor through modulation of salt bridge strength. J Med Chem 59: 6470–6479.    

107. Batyuk A, Galli L, Ishchenko A, et al. (2016) Native phasing of x-ray free-electron laser data for a G protein-coupled receptor. Sci Adv 2: e1600292.    

108. Carpenter B, Nehme R, Warne T, et al. (2016) Structure of the adenosine A(2A) receptor bound to an engineered G protein. Nature 536: 104–107.    

109. Sun B, Bachhawat P, Chu ML, et al. (2017) Crystal structure of the adenosine A2A receptor bound to an antagonist reveals a potential allosteric pocket. Proc Natl Acad Sci USA 114: 2066–2071.    

110. Hanson MA, Roth CB, Jo E, et al. (2012) Crystal structure of a lipid G protein-coupled receptor. Science 335: 851–855.    

111. Chrencik JE, Roth CB, Terakado M, et al. (2015) Crystal structure of antagonist bound human lysophosphatidic acid receptor 1. Cell 161: 1633–1643.    

112. Hua T, Vemuri K, Pu M, et al. (2016) Crystal structure of the human cannabinoid receptor CB1. Cell 167: 750–762.    

113. Shao Z, Yin J, Chapman K, et al. (2016) High-resolution crystal structure of the human CB1 cannabinoid receptor. Nature.

114. White JF, Noinaj N, Shibata Y, et al. (2012) Structure of the agonist-bound neurotensin receptor. Nature 490: 508–513.    

115. Egloff P, Hillenbrand M, Klenk C, et al. (2014) Structure of signaling-competent neurotensin receptor 1 obtained by directed evolution in Escherichia coli. Proc Natl Acad Sci USA 111: E655–E662.    

116. Krumm BE, White JF, Shah P, et al. (2015) Structural prerequisites for G-protein activation by the neurotensin receptor. Nat Commun 6: 7895.    

117. Krumm BE, Lee S, Bhattacharya S, et al. (2016) Structure and dynamics of a constitutively active neurotensin receptor. Sci Rep 6: 38564.    

118. Yin J, Mobarec JC, Kolb P, et al. (2015) Crystal structure of the human OX2 orexin receptor bound to the insomnia drug suvorexant. Nature 519: 247–250.

119. Gayen A, Goswami SK, Mukhopadhyay C (2011) NMR evidence of GM1-induced conformational change of Substance P using isotropic bicelles. Biochim Biophys Acta 1808: 127–139.    

120. Shihoya W, Nishizawa T, Okuta A, et al. (2016) Activation mechanism of endothelin ETB receptor by endothelin-1. Nature 537: 363–368.    

121. Park SH, Das BB, Casagrande F, et al. (2012) Structure of the chemokine receptor CXCR1 in phospholipid bilayers. Nature 491: 779–783.

122. Zheng Y, Qin L, Zacarias NV, et al. (2016) Structure of CC chemokine receptor 2 with orthosteric and allosteric antagonists. Nature 540: 458–461.    

123. Wu B, Chien EY, Mol CD, et al. (2010) Structures of the CXCR4 chemokine GPCR with small-molecule and cyclic peptide antagonists. Science 330: 1066–1071.    

124. Qin L, Kufareva I, Holden LG, et al. (2015) Structural biology. Crystal structure of the chemokine receptor CXCR4 in complex with a viral chemokine. Science 347: 1117–1122.

125. Tan Q, Zhu Y, Li J, et al. (2013) Structure of the CCR5 chemokine receptor-HIV entry inhibitor maraviroc complex. Science 341: 1387–1390.    

126. Oswald C, Rappas M, Kean J, et al. (2016) Intracellular allosteric antagonism of the CCR9 receptor. Nature 540: 462–465.    

127. Miller RL, Thompson AA, Trapella C, et al. (2015) The importance of ligand-receptor conformational pairs in stabilization: Spotlight on the N/OFQ G protein-coupled receptor. Structure 23: 2291–2299.    

128. Wu H, Wacker D, Mileni M, et al. (2012) Structure of the human kappa-opioid receptor in complex with JDTic. Nature 485: 327–332.    

129. Manglik A, Kruse AC, Kobilka TS, et al. (2012) Crystal structure of the mu-opioid receptor bound to a morphinan antagonist. Nature 485: 321–326.    

130. Huang W, Manglik A, Venkatakrishnan AJ, et al. (2015) Structural insights into micro-opioid receptor activation. Nature 524: 315–321.    

131. Granier S, Manglik A, Kruse AC, et al. (2012) Structure of the delta-opioid receptor bound to naltrindole. Nature 485: 400–404.    

132. Fenalti G, Giguere PM, Katritch V, et al. (2014) Molecular control of delta-opioid receptor signaling. Nature 506: 191–196.    

133. Fenalti G, Zatsepin NA, Betti C, et al. (2015) Structural basis for bifunctional peptide recognition at human delta-opioid receptor. Nat Struct Mol Biol 22: 265–268.    

134. Zhang H, Unal H, Gati C, et al. (2015) Structure of the Angiotensin receptor revealed by serial femtosecond crystallography. Cell 161: 833–844.    

135. Zhang H, Unal H, Desnoyer R, et al. (2015) Structural basis for ligand recognition and functional selectivity at angiotensin receptor. J Biol Chem 290: 29127–29139.    

136. Zhang H, Han GW, Batyuk A, et al. (2017) Structural basis for selectivity and diversity in angiotensin II receptors. Nature.

137. Burg JS, Ingram JR, Venkatakrishnan AJ, et al. (2015) Structural biology. Structural basis for chemokine recognition and activation of a viral G protein-coupled receptor. Science 347: 1113–1117.

138. Zhang D, Gao ZG, Zhang K, et al. (2015) Two disparate ligand-binding sites in the human P2Y1 receptor. Nature 520: 317–321.    

139. Zhang J, Zhang K, Gao ZG, et al. (2014) Agonist-bound structure of the human P2Y12 receptor. Nature 509: 119–122.    

140. Zhang C, Srinivasan Y, Arlow DH, et al. (2012) High-resolution crystal structure of human protease-activated receptor 1. Nature 492: 387–392.    

141. Srivastava A, Yano J, Hirozane Y, et al. (2014) High-resolution structure of the human GPR40 receptor bound to allosteric agonist TAK-875. Nature 513: 124–127.    

142. Siu FY, He M, de Graaf C, et al. (2013) Structure of the human glucagon class B G-protein-coupled receptor. Nature 499: 444–449.    

143. Jazayeri A, Dore AS, Lamb D, et al. (2016) Extra-helical binding site of a glucagon receptor antagonist. Nature 533: 274–277.    

144. Hollenstein K, Kean J, Bortolato A, et al. (2013) Structure of class B GPCR corticotropin-releasing factor receptor 1. Nature 499: 438–443.    

145. Dore AS, Bortolato A, Hollenstein K, et al. (2017) Decoding corticotropin-releasing factor receptor type 1 crystal structures. Curr Mol Pharmacol: Epub ahead of print, DOI: 10.2174/1874467210666170110114727.

146. Wu H, Wang C, Gregory KJ, et al. (2014) Structure of a class C GPCR metabotropic glutamate receptor 1 bound to an allosteric modulator. Science 344: 58–64.    

147. Christopher JA, Aves SJ, Bennett KA, et al. (2015) Fragment and structure-based drug discovery for a class C GPCR: Discovery of the mGlu5 negative allosteric modulator HTL14242 (3-Chloro-5-[6-(5-fluoropyridin-2-yl)pyrimidin-4-yl]benzonitrile). J Med Chem 58: 6653–6664.    

148. Wang C, Wu H, Evron T, et al. (2014) Structural basis for Smoothened receptor modulation and chemoresistance to anticancer drugs. Nat Commun 5: 4355.

149. Byrne EF, Sircar R, Miller PS, et al. (2016) Structural basis of Smoothened regulation by its extracellular domains. Nature 535: 517–522.    

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

151. Shonberg J, Kling RC, Gmeiner P, et al. (2015) GPCR crystal structures: Medicinal chemistry in the pocket. Bioorg Med Chem 23: 3880–3906.    

152. Attwood TK, Findlay JB (1993) Design of a discriminating fingerprint for G-protein-coupled receptors. Protein Eng 6: 167–176.    

153. Chee MS, Satchwell SC, Preddie E, et al. (1990) Human cytomegalovirus encodes three G protein-coupled receptor homologues. Nature 344: 774–777.    

154. Attwood TK, Findlay JB (1994) Fingerprinting G-protein-coupled receptors. Protein Eng 7: 195–203.    

155. Strader CD, Sigal IS, Dixon RA (1989) Structural basis of beta-adrenergic receptor function. FASEB J 3: 1825–1832.

156. Liapakis G, Ballesteros JA, Papachristou S, et al. (2000) The forgotten serine. A critical role for Ser-2035.42 in ligand binding to and activation of the beta 2-adrenergic receptor. J Biol Chem 275: 37779–37788.

157. Swaminath G, Xiang Y, Lee TW, et al. (2004) Sequential binding of agonists to the beta2 adrenoceptor. Kinetic evidence for intermediate conformational states. J Biol Chem 279: 686–691.

158. Baldwin JM (1994) Structure and function of receptors coupled to G proteins. Curr Opin Cell Biol 6: 180–190.    

159. Tyndall JD, Sandilya R (2005) GPCR agonists and antagonists in the clinic. Med Chem 1: 405–421.    

160. Jacoby E, Bouhelal R, Gerspacher M, et al. (2006) The 7 TM G-protein-coupled receptor target family. Chem Med Chem 1: 761–782.

161. Spiss CK, Maze M (1985) Adrenoreceptors. Anaesthesist 34: 1–10.

162. Civelli O, Reinscheid RK, Zhang Y, et al. (2013) G protein-coupled receptor deorphanizations. Annu Rev Pharmacol Toxicol 53: 127–146.    

163. Barst RJ, Langleben D, Frost A, et al. (2004) Sitaxsentan therapy for pulmonary arterial hypertension. Am J Respir Crit Care Med 169: 441–447.    

164. Kotake T, Usami M, Akaza H, et al. (1999) Goserelin acetate with or without antiandrogen or estrogen in the treatment of patients with advanced prostate cancer: a multicenter, randomized, controlled trial in Japan. Zoladex Study Group. Jpn J Clin Oncol 29: 562–570.    

165. Onuffer JJ, Horuk R (2002) Chemokines, chemokine receptors and small-molecule antagonists: recent developments. Trends Pharmacol Sci 23: 459–467.    

166. Fatkenheuer G, Pozniak AL, Johnson MA, et al. (2005) Efficacy of short-term monotherapy with maraviroc, a new CCR5 antagonist, in patients infected with HIV-1. Nat Med 11: 1170–1172.    

167. Lu M, Wu B (2016) Structural studies of G protein-coupled receptors. IUBMB Life 68: 894–903.    

168. Strotmann R, Schrock K, Boselt I, et al. (2011) Evolution of GPCR: change and continuity. Mol Cell Endocrinol 331: 170–178.    

169. Ballesteros JA, Weinstein H (1995) Integrated methods for the construction of three-dimensional models and computational probing of structure-function relations in G protein-coupled receptors. Method Neurosci 25: 366–428.    

170. Zhang D, Weinstein H (1994) Polarity conserved positions in transmembrane domains of G-protein coupled receptors and bacteriorhodopsin. FEBS Lett 337: 207–212.    

171. Katritch V, Fenalti G, Abola EE, et al. (2014) Allosteric sodium in class A GPCR signaling. Trends Biochem Sci 39: 233–244.    

172. Bjarnadottir TK, Geirardsdottir K, Ingemansson M, et al. (2007) Identification of novel splice variants of Adhesion G protein-coupled receptors. Gene 387: 38–48.    

173. Lin HH, Chang GW, Davies JQ, et al. (2004) Autocatalytic cleavage of the EMR2 receptor occurs at a conserved G protein-coupled receptor proteolytic site motif. J Biol Chem 279: 31823–31832.    

174. Isberg V, Vroling B, Van DKR, et al. (2014) GPCRDB: an information system for G protein-coupled receptors. Nucleic Acids Res 42: D422–D425.    

175. Gasparini F, Kuhn R, Pin JP (2002) Allosteric modulators of group I metabotropic glutamate receptors: novel subtype-selective ligands and therapeutic perspectives. Curr Opin Pharmacol 2: 43–49.    

176. Malherbe P, Kratochwil N, Zenner MT, et al. (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.    

177. Litschig S, Gasparini F, Rueegg D, et al. (1999) CPCCOEt, a noncompetitive metabotropic glutamate receptor 1 antagonist, inhibits receptor signaling without affecting glutamate binding. Mol Pharmacol 55: 453–461.

178. Silve C, Petrel C, Leroy C, et al. (2005) Delineating a Ca2+ binding pocket within the venus flytrap module of the human calcium-sensing receptor. J Biol Chem 280: 37917–37923.    

179. Hermans E, Challiss RA (2001) Structural, signalling and regulatory properties of the group I metabotropic glutamate receptors: prototypic family C G-protein-coupled receptors. Biochem J 359: 465–484.    

180. Nakanishi S (1992) Molecular diversity of glutamate receptors and implications for brain function. Science 258: 597–603.    

181. Riedel G, Platt B, Micheau J (2003) Glutamate receptor function in learning and memory. Behav Brain Res 140: 1–47.    

182. Kunishima N, Shimada Y, Tsuji Y, et al. (2000) Structural basis of glutamate recognition by a dimeric metabotropic glutamate receptor. Nature 407: 971–977.    

183. Niswender CM, Conn PJ (2010) Metabotropic glutamate receptors: physiology, pharmacology, and disease. Annu Rev Pharmacol Toxicol 50: 295–322.    

184. Bhanot P, Brink M, Samos CH, et al. (1996) A new member of the frizzled family from Drosophila functions as a Wingless receptor. Nature 382: 225–230.    

185. Murone M, Rosenthal A, de Sauvage FJ (1999) Sonic hedgehog signaling by the patched-smoothened receptor complex. Curr Biol 9: 76–84.    

186. Chen CM, Strapps W, Tomlinson A, et al. (2004) Evidence that the cysteine-rich domain of Drosophila Frizzled family receptors is dispensable for transducing Wingless. Proc Natl Acad Sci USA 101: 15961–15966.    

187. Nakano Y, Nystedt S, Shivdasani AA, et al. (2004) Functional domains and sub-cellular distribution of the Hedgehog transducing protein Smoothened in Drosophila. Mech Dev 121: 507–518.    

188. Isberg V, de Graaf C, Bortolato A, et al. (2015) Generic GPCR residue numbers-Aligning topology maps minding the gaps. Trends Pharmacol Sci 36: 22–31.    

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