1932

Abstract

G protein–coupled receptors (GPCRs) mediate the majority of cellular responses to external stimuli. Upon activation by a ligand, the receptor binds to a partner heterotrimeric G protein and promotes exchange of GTP for GDP, leading to dissociation of the G protein into α and βγ subunits that mediate downstream signals. GPCRs can also activate distinct signaling pathways through arrestins. Active states of GPCRs form by small rearrangements of the ligand-binding, or orthosteric, site that are amplified into larger conformational changes. Molecular understanding of the allosteric coupling between ligand binding and G protein or arrestin interaction is emerging from structures of several GPCRs crystallized in inactive and active states, spectroscopic data, and computer simulations. The coupling is loose, rather than concerted, and agonist binding does not fully stabilize the receptor in an active conformation. Distinct intermediates whose populations are shifted by ligands of different efficacies underlie the complex pharmacology of GPCRs.

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2018-06-20
2024-06-17
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Literature Cited

  1. 1.  Maguire ME, Van Arsdale PM, Glilman AG 1976. An agonist-specific effect of guanine nucleotides on binding to the beta adrenergic receptor. Mol. Pharmacol. 12:332–39
    [Google Scholar]
  2. 2.  De Lean A, Stadel JM, Lefkowitz RJ 1980. A ternary complex model explains the agonist-specific binding properties of the adenylate cyclase-coupled β-adrenergic receptor. J. Biol. Chem. 255:7108–17
    [Google Scholar]
  3. 3.  Cui Q, Karplus M 2008. Allostery and cooperativity revisited. Protein Sci 17:1295–307
    [Google Scholar]
  4. 4.  Nussinov R, Ma B, Tsai CJ 2014. Multiple conformational selection and induced fit events take place in allosteric propagation. Biophys. Chem. 186:22–30
    [Google Scholar]
  5. 5.  Henzler-Wildman K, Kern D 2007. Dynamic personalities of proteins. Nature 450:964–72
    [Google Scholar]
  6. 6.  Fredriksson R, Langerstrom MC, Lundin LG, Schioth HB 2003. The G-protein-coupled receptors in the human genome form five main families. Phylogenetic analysis, paralogon groups, and fingerprints. Mol. Pharmacol. 63:1256–72
    [Google Scholar]
  7. 7.  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. Methods Neurosci 25:366–428
    [Google Scholar]
  8. 8.  Palczewski K, Kumasaka T, Hori T, Behnke CA, Motoshima H et al. 2000. Crystal structure of rhodopsin: a G protein-coupled receptor. Science 289:5480739–45
    [Google Scholar]
  9. 9.  Faham S, Bowie JU 2002. Bicelle crystallization: a new method for crystallizing membrane proteins yields a monomeric bacteriorhodopsin structure. J. Mol. Biol. 316:11–6
    [Google Scholar]
  10. 10.  Rasmussen SGF, Choi H-J, Rosenbaum DM, Kobilka TS, Thian FS et al. 2007. Crystal structure of the human β2 adrenergic G-protein-coupled receptor. Nature 450:7168383–87
    [Google Scholar]
  11. 11.  Caffrey M. 2009. Crystallizing membrane proteins for structure determination: use of lipidic mesophases. Annu. Rev. Biophys. 38:29–51
    [Google Scholar]
  12. 12.  Magnani F, Serrano-Vega MJ, Shibata Y, Abdul-Hussein S, Lebon G et al. 2016. A mutagenesis and screening strategy to generate optimally thermostabilized membrane proteins for structural studies. Nat. Protoc. 11:1554–71
    [Google Scholar]
  13. 13.  Zou Y, Weis WI, Kobilka BK 2012. N-terminal T4 lysozyme fusion facilitates crystallization of a G protein coupled receptor. PLOS ONE 7:10e46039
    [Google Scholar]
  14. 14.  Rosenbaum DM, Cherezov V, Hanson MA, Rasmussen SGF, Thian FS et al. 2007. GPCR engineering yields high-resolution structural insights into β2-adrenergic receptor function. Science 318:58541266–73
    [Google Scholar]
  15. 15.  Chun E, Thompson AA, Lu W, Roth CB, Griffith MT et al. 2012. Fusion partner toolchest for the stabilization and crystallization of G protein-coupled receptors. Structure 20:967–76
    [Google Scholar]
  16. 16.  Cherezov V, Rosenbaum DM, Hanson MA, Rasmussen SGF, Thian FS et al. 2007. High-resolution crystal structure of an engineered human β2-adrenergic G protein–coupled receptor. Science 318:58541258–65
    [Google Scholar]
  17. 17.  Lebon G, Warne T, Edwards PC, Bennett K, Langmead CJ et al. 2011. Agonist-bound adenosine A2A receptor structures reveal common features of GPCR activation. Nature 474:521–25
    [Google Scholar]
  18. 18.  Xu F, Wu H, Katritch V, Han GW, Jacobson KA et al. 2011. Structure of an agonist-bound human A2A adenosine receptor. Science 332:322–27
    [Google Scholar]
  19. 19.  Eddy MT, Didenko T, Stevens RC, Wuthrich K 2016. β2-Adrenergic receptor conformational response to fusion protein in the third intracellular loop. Structure 24:2190–97
    [Google Scholar]
  20. 20.  Kruse AC, Hu J, Pan AC, Arlow DH, Rosenbaum DM et al. 2012. Structure and dynamics of the M3 muscarinic acetylcholine receptor. Nature 482:7386552–56
    [Google Scholar]
  21. 21.  DeVree BT, Mahoney JP, Vélez-Ruiz GA, Rasmussen SGF, Kuszak AJ et al. 2016. Allosteric coupling from G protein to the agonist-binding pocket in GPCRs. Nature 535:182–86
    [Google Scholar]
  22. 22.  Venkatakrishnan AJ, Deupi X, Lebon G, Tate CG, Schertler Babu MM 2013. Molecular signatures of G-protein-coupled receptors. Nature 494:185–88
    [Google Scholar]
  23. 23.  Rosenbaum DM, Zhang C, Lyons J, Holl R, Aragao D et al. 2011. Structure and function of an irreversible agonist-β2 adrenoceptor complex. Nature 469:7329236–40
    [Google Scholar]
  24. 24.  Carpenter B, Nehme R, Warne T, Leslie AGW, Tate CG 2016. Structure of the adenosine A2A receptor bound to an engineered G protein. Nature 536:104–7
    [Google Scholar]
  25. 25.  Scheerer P, Park JH, Hildebrand PW, Kim YJ, Krauss N et al. 2008. Crystal structure of opsin in its G-protein-interacting conformation. Nature 455:497–502
    [Google Scholar]
  26. 26.  Choe HW, Kim YJ, Park JH, Morizumi T, Pai EF et al. 2011. Crystal structure of metarhodopsin II. Nature 471:651–55
    [Google Scholar]
  27. 27.  Standfuss J, Edwards PC, D'Antona A, Fransen M, Xie G et al. 2011. The structural basis of agonist-induced activation in constitutively active rhodopsin. Nature 471:656–60
    [Google Scholar]
  28. 28.  Manglik A, Kobilka BK, Steyaert J 2017. Nanobodies to study G protein–coupled receptor structure and function. Annu. Rev. Pharmacol. Toxicol. 57:19–37
    [Google Scholar]
  29. 29.  Rasmussen SG, Choi H-J, Fung JJ, Pardon E, Casarosa P et al. 2011. Structure of a nanobody-stabilized active state of the β2 adrenoceptor. Nature 469:7329175–80
    [Google Scholar]
  30. 30.  Steyaert J, Kobilka BK 2011. Nanobody stabilization of G protein-coupled receptor conformational states. Curr. Opin. Struct. Biol. 21:567–72
    [Google Scholar]
  31. 31.  Ring AM, Manglik A, Kruse AC, Enos MD, Weis WI et al. 2013. Adrenaline-activated structure of β2-adrenoceptor stabilized by an engineered nanobody. Nature 502:7472575–79
    [Google Scholar]
  32. 32.  Kruse AC, Ring AM, Manglik A, Hu J, Hu K et al. 2013. Activation and allosteric modulation of a muscarinic acetylcholine receptor. Nature 504:7478101–6
    [Google Scholar]
  33. 33.  Burg JS, Ingram JR, Venkatakrishnan AJ, Jude KM, Dukkipati A et al. 2015. Structural basis for chemokine recognition and activation of a viral G protein-coupled receptor. Science 347:1113–17
    [Google Scholar]
  34. 34.  Huang W, Maglik A, Venkatakrishnan AJ, Laeremans T, Feinberg EN et al. 2015. Structural insights into μ-opioid receptor activation. Nature 524:315–21
    [Google Scholar]
  35. 35.  Liang YL, Khoushouei M, Radjainia M, Zhang Y, Glukhova A et al. 2017. Phase-plate cryo-EM structure of a class B GPCR–G-protein complex. Nature 546:118–23
    [Google Scholar]
  36. 36.  Zhang Y, Sun B, Feng D, Hu H, Chu M et al. 2017. Cryo-EM structure of the activated GLP-1 receptor in complex with a G protein. Nature 546:248–53
    [Google Scholar]
  37. 37.  Venkatakrishnan AJ, Deupi X, Lebon G, Heydenreich FM, Flock T et al. 2016. Diverse activation pathways in class A GPCRs converge near the G protein-coupling region. Nature 536:484–87
    [Google Scholar]
  38. 38.  Gether U, Seifert R, Ballesteros JA, Sanders-Bush E, Weinstein H, Kobilka BK 1997. Structural instability of a constitutively active G protein-coupled receptor. J. Biol. Chem. 272:2587–90
    [Google Scholar]
  39. 39.  Moukhametzianov R, Warne T, Edwards PC, Serrano-Vega MJ, Leslie AGW et al. 2011. Two distinct conformations of helix 6 observed in antagonist-bound structures of a β1-adrenergic receptor. PNAS 108:8228–32
    [Google Scholar]
  40. 40.  Dror RO, Arlow DH, Borhani DW, Jensen , Piana S, Shaw DE 2009. Identification of two distinct inactive conformations of the β2-adrenergic receptor reconciles structural and biochemical observations. PNAS 106:4689–94
    [Google Scholar]
  41. 41.  Romo TD, Grossfield A, Pitman MC 2010. Concerted interconversion between ionic lock substates of the β2 adrenergic receptor revealed by microsecond timescale molecular dynamics. Biophys. J. 98:76–84
    [Google Scholar]
  42. 42.  Ballesteros JA, Jensen AD, Liapakis G, Rasmussen SGF, Shi L et al. 2001. Activation of the β2-adrenergic receptor involves disruption of an ionic lock between the cytoplasmic ends of transmembrane segments 3 and 6. J. Biol. Chem. 276:3129171–77
    [Google Scholar]
  43. 43.  Valentin-Hensen L, Groenen M, Nygaard R, Frimurer TM, Holliday ND, Schwartz TW 2012. The arginine of the DRY motif in transmembrane segment III functions as a balancing micro-switch in the activation of the β2-adrenergic receptor. J. Biol. Chem. 287:31973–82
    [Google Scholar]
  44. 44.  Rasmussen SG, DeVree BT, Zou Y, Kruse AC, Chung KY et al. 2011. Crystal structure of the β2 adrenergic receptor–Gs protein complex. Nature 477:7366549–55
    [Google Scholar]
  45. 45.  Warne T, Moukhametzianov R, Baker JG, Nehmé R, Edwards PC et al. 2011. The structural basis for agonist and partial agonist action on a β1-adrenergic receptor. Nature 469:241–44
    [Google Scholar]
  46. 46.  Dror RO, Arlow DH, Maragakis P, Mildorf TJ, Pan AC et al. 2011. Activation mechanism of the β2-adrenergic receptor. PNAS 108:18684–89
    [Google Scholar]
  47. 47.  Bhattacharya S, Vaidehi N 2014. Differences in allosteric communication pipelines in the inactive and active states of a GPCR. Biophys. J. 107:422–34
    [Google Scholar]
  48. 48.  Frauenfelder H, Sligar SG, Wolynes PG 1991. The energy landscapes and motions of proteins. Science 254:1598–603
    [Google Scholar]
  49. 49.  West GM, Chien EYT, Katrich V, Gatchalian J, Chalmers MJ et al. 2011. Ligand-dependent perturbation of the conformational ensemble for the GPCR β2 adrenergic receptor revealed by HDX. Structure 19:1424–32
    [Google Scholar]
  50. 50.  Kim TH, Chung KY, Manglik A, Hansen AL, Dror RO et al. 2013. The role of ligands on the equilibria between functional states of a G protein-coupled receptor. J. Am. Chem. Soc. 135:9465–74
    [Google Scholar]
  51. 51.  Altenbach C, Kusnetzow AK, Ernst OP, Hofmann KP, Hubbell WL 2008. High-resolution distance mapping in rhodopsin reveals the pattern of helix movement due to activation. PNAS 105:217439–44
    [Google Scholar]
  52. 52.  Klare JP. 2013. Site-directed spin labeling EPR spectroscopy in protein research. Biol. Chem. 394:1281–300
    [Google Scholar]
  53. 53.  Ghanouni P, Steenhuis JJ, Farrens DL, Kobilka BK 2001. Agonist-induced conformational changes in the G-protein-coupling domain of the β2 adrenergic receptor. PNAS 98:115997–6002
    [Google Scholar]
  54. 54.  Yao X, Parnot C, Deupi X, Ratnala VRP, Swaminath G et al. 2006. Coupling ligand structure to specific conformational switches in the β2-adrenoceptor. Nat. Chem. Biol. 2:8417–22
    [Google Scholar]
  55. 55.  Horst R, Liu JJ, Stevens RC, Wuthrich K 2013. β2-Adrenergic receptor activation by agonists studied with 19F NMR spectroscopy. Angew. Chem. 52:4110762–65
    [Google Scholar]
  56. 56.  Liu JJ, Horst R, Katrich V, Stevens RC, Wuthrich K 2012. Biased signaling pathways in β2-adrenergic receptor characterized by 19F-NMR. Science 335:1106–10
    [Google Scholar]
  57. 57.  Lamichhane R, Liu JJ, Pljevaljcic G, White KL, van der Schans E et al. 2015. Single-molecule view of basal activity and activation mechanism of the G protein-coupled receptor β2AR. PNAS 112:14254–59
    [Google Scholar]
  58. 58.  Ye L, Van Eps N, Zimmer M, Ernst OP, Prosser RS 2016. Activation of the A2A adenosine G-protein-coupled receptor by conformational selection. Nature 533:265–68
    [Google Scholar]
  59. 59.  Manglik A, Kim TH, Masureel M, Altenbach C, Yang Z et al. 2015. Structural insights into the dynamic process of β2-adrenergic receptor signaling. Cell 161:1101–11
    [Google Scholar]
  60. 60.  Chung KY, Kim TH, Manglik A, Alvares R, Kobilka BK, Prosser RS. 2012 Role of detergents in conformational exchange of a G protein-coupled receptor. J. Biol. Chem. 287:36305–11
    [Google Scholar]
  61. 61.  Gregorio GG, Masureel M, Hilger D, Terry DS, Juette M et al. 2017. Single-molecule analysis of ligand efficacy in β2AR–G-protein activation. Nature 547:68–73
    [Google Scholar]
  62. 62.  Kofuku Y, Ueda T, Okude J, Shiraishi Y, Kondo K et al. 2012. Efficacy of the β2-adrenergic receptor is determined by conformational equilibrium in the transmembrane region. Nat. Commun. 3:1045
    [Google Scholar]
  63. 63.  Nygaard R, Zhou Y, Dror RO, Mildorf TJ, Arlow DH et al. 2013. The dynamic process of β2-adrenergic receptor activation. Cell 152:532–42
    [Google Scholar]
  64. 64.  Kofuku Y, Ueda T, Okude J, Shiraishi Y, Kondo K et al. 2014. Functional dynamics of deuterated β2-adrenergic receptor in lipid bilayers revealed by NMR spectroscopy. Angew. Chem. 53:4913376–79
    [Google Scholar]
  65. 65.  Mahmood I, Liu X, Neya S, Hoshino T 2013. Influence of lipid composition on the structural stability of g-protein coupled receptor. Chem. Pharm. Bull. 61:426–37
    [Google Scholar]
  66. 66.  Dawaliby R, Trubbia C, Delporte C, Masureel M, Van Antwerpen P et al. 2016. Allosteric regulation of G protein-coupled receptor activity by phospholipids. Nat. Chem. Biol. 12:35–39
    [Google Scholar]
  67. 67.  Isogai S, Deupi X, Opitz C, Heydenreich FM, Tsai C-J et al. 2016. Backbone NMR reveals allosteric signal transduction networks in the β1-adrenergic receptor. Nature 530:237–41
    [Google Scholar]
  68. 68.  Sounier R, Mas C, Steyaert J, Laeremans T, Manglik A et al. 2015. Propagation of conformational changes during μ-opioid receptor activation. Nature 524:375–78
    [Google Scholar]
  69. 69.  Staus DP, Strachan RT, Manglik A, Biswaranjan P, Kahsai AW et al. 2016. Allosteric nanobodies reveal the dynamic range and diverse mechanisms of G-protein-coupled receptor activation. Nature 535:448–52
    [Google Scholar]
  70. 70.  Kang Y, Zhou XE, Gao X, He Y, Liu W et al. 2015. Crystal structure of rhodopsin bound to arrestin by femtosecond X-ray laser. Nature 523:7562561–67
    [Google Scholar]
  71. 71.  Zhou XE, He Y, de Waal PW, Gao X, Kang Y et al. 2017. Identification of phosphorylation codes for arrestin recruitment by G protein-coupled receptors. Cell 170:457–69
    [Google Scholar]
  72. 72.  Komolov KE, Du Y, Duc NM, Betz RM, Rodrigues JPGLM et al. 2017. Structural and functional analysis of a β2-adrenergic receptor complex with GRK5. Cell 169:407–421
    [Google Scholar]
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