Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Molecular signatures of G-protein-coupled receptors

Abstract

G-protein-coupled receptors (GPCRs) are physiologically important membrane proteins that sense signalling molecules such as hormones and neurotransmitters, and are the targets of several prescribed drugs. Recent exciting developments are providing unprecedented insights into the structure and function of several medically important GPCRs. Here, through a systematic analysis of high-resolution GPCR structures, we uncover a conserved network of non-covalent contacts that defines the GPCR fold. Furthermore, our comparative analysis reveals characteristic features of ligand binding and conformational changes during receptor activation. A holistic understanding that integrates molecular and systems biology of GPCRs holds promise for new therapeutics and personalized medicine.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Time-line of GPCR structures.
Figure 2: Diversity in the secondary structure elements of GPCRs in the extracellular and intracellular regions.
Figure 3: Consensus scaffold of non-covalent contacts in GPCRs.
Figure 4: Ligand-binding pocket in class A GPCRs.
Figure 5: Characterization of G-protein-binding region within TM helices of GPCRs.
Figure 6: Structural and functional hub role of TM3.

References

  1. 1

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

    CAS  PubMed  Google Scholar 

  2. 2

    Tate, C. G., Schertler, G. F. & Engineering, G. Protein-coupled receptors to facilitate their structure determination. Curr. Opin. Struct. Biol. 19, 386–395 (2009)

    CAS  PubMed  Google Scholar 

  3. 3

    Cherezov, V. et al. High-resolution crystal structure of an engineered human β2-adrenergic G protein-coupled receptor. Science 318, 1258–1265 (2007)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  4. 4

    Rosenbaum, D. M. et al. GPCR engineering yields high-resolution structural insights into β2-adrenergic receptor function. Science 318, 1266–1273 (2007)Description of the T4 lysozyme fusion strategy that led to the first high-resolution β 2 -AR structure using the lipidic cubic phase crystallization technique3, which has been subsequently used to facilitate the crystallization of many other GPCRs.

    ADS  CAS  PubMed  Google Scholar 

  5. 5

    Thompson, A. A. et al. Structure of the nociceptin/orphanin FQ receptor in complex with a peptide mimetic. Nature 485, 395–399 (2012)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  6. 6

    Rasmussen, S. G. et al. Crystal structure of the human β2 adrenergic G-protein-coupled receptor. Nature 450, 383–387 (2007)

    ADS  CAS  PubMed  Google Scholar 

  7. 7

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

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  8. 8

    Rasmussen, S. G. et al. Structure of a nanobody-stabilized active state of the β2 adrenoceptor. Nature 469, 175–180 (2011)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  9. 9

    Rasmussen, S. G. et al. Crystal structure of the β2 adrenergic receptor–Gs protein complex. Nature 477, 549–555 (2011)A seminal paper showing how an activated GPCR binds to a heterotrimeric G protein, which also suggests a mechanism for how the G protein becomes activated.

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  10. 10

    Warne, T. et al. Structure of a β1-adrenergic G-protein-coupled receptor. Nature 454, 486–491 (2008)This paper describes the first structure determined through the implementation of systematic scanning mutagenesis to develop a thermostabilized receptor that can be co-crystallized in the presence of even weakly binding ligands32.

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  11. 11

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

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12

    Doré, A. S. et al. Structure of the adenosine A2A receptor in complex with ZM241385 and the xanthines XAC and caffeine. Structure 19, 1283–1293 (2011)

    PubMed  PubMed Central  Google Scholar 

  13. 13

    Standfuss, J. et al. The structural basis of agonist-induced activation in constitutively active rhodopsin. Nature 471, 656–660 (2011)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  14. 14

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

    ADS  CAS  PubMed  Google Scholar 

  15. 15

    Caffrey, M. Crystallizing membrane proteins for structure determination: use of lipidic mesophases. Annu. Rev. Biophys. 38, 29–51 (2009)

    CAS  PubMed  Google Scholar 

  16. 16

    Chae, P. S. et al. Maltose–neopentyl glycol (MNG) amphiphiles for solubilization, stabilization and crystallization of membrane proteins. Nature Methods 7, 1003–1008 (2010)

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17

    Moukhametzianov, R. et al. Protein crystallography with a micrometre-sized synchrotron-radiation beam. Acta Crystallogr. D 64, 158–166 (2008)

    CAS  PubMed  Google Scholar 

  18. 18

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

    ADS  CAS  PubMed  Google Scholar 

  19. 19

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

    ADS  CAS  PubMed  Google Scholar 

  20. 20

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

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  21. 21

    Kruse, A. C. et al. Structure and dynamics of the M3 muscarinic acetylcholine receptor. Nature 482, 552–556 (2012)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  22. 22

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

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23

    Chien, E. Y. et al. Structure of the human dopamine D3 receptor in complex with a D2/D3 selective antagonist. Science 330, 1091–1095 (2010)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  24. 24

    Jaakola, V. P. et al. The 2.6 angstrom crystal structure of a human A2A adenosine receptor bound to an antagonist. Science 322, 1211–1217 (2008)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  25. 25

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

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  26. 26

    Wu, H. et al. Structure of the human κ-opioid receptor in complex with JDtic. Nature 485, 327–332 (2012)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  27. 27

    Manglik, A. et al. Crystal structure of the μ-opioid receptor bound to a morphinan antagonist. Nature (2012)

  28. 28

    Granier, S. et al. Structure of the δ-opioid receptor bound to naltrindole. Nature 485, 400–404 (2012)This paper, along with the three accompanying papers5,26,27, allows a detailed comparison of all the major opioid receptors, which is an excellent starting point for structure-based development of subtype-specific inhibitors for pain relief.

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  29. 29

    White, J. F. et al. Structure of the agonist-bound neurotensin receptor. Nature 490, 508–513 (2012)This is the first description of a GPCR bound to a peptide agonist, which shows that agonist-specific interactions in NTSR1 occur closer to the extracellular surface than observed in other receptors.

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  30. 30

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

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  31. 31

    Hanson, M. A. et al. Crystal structure of a lipid G protein-coupled receptor. Science 335, 851–855 (2012)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  32. 32

    Park, S. H. et al. Structure of the chemokine receptor CXCR1 in phospholipid bilayers. Nature 491, 779–783 (2012)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  33. 33

    Choe, H. W. et al. Crystal structure of metarhodopsin II. Nature 471, 651–655 (2011)

    ADS  CAS  PubMed  Google Scholar 

  34. 34

    Rosenbaum, D. M. et al. Structure and function of an irreversible agonist-β2 adrenoceptor complex. Nature 469, 236–240 (2011)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  35. 35

    Warne, T. et al. The structural basis for agonist and partial agonist action on a β1-adrenergic receptor. Nature 469, 241–244 (2011)Comparison of β 1 -AR structures bound to different agonists and partial agonists suggests reasons for their different efficacies and why inverse agonists actively inhibit the activation of β-ARs.

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  36. 36

    Warne, T., Edwards, P. C., Leslie, A. G. & Tate, C. G. Crystal structures of a stabilized β1-adrenoceptor bound to the biased agonists bucindolol and carvedilol. Structure 20, 841–849 (2012)

    CAS  PubMed  Google Scholar 

  37. 37

    Xu, F. et al. Structure of an agonist-bound human A2A adenosine receptor. Science 332, 322–327 (2011)Along with ref. 11, this paper describes the structure of A 2A R in an agonist-bound active-like state that shows common features of activation compared to β 2 -AR.

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  38. 38

    Scheerer, P. et al. Crystal structure of opsin in its G-protein-interacting conformation. Nature 455, 497–502 (2008)The structure of opsin bound to the C-terminal fragment of transducin was the first insight into how an activated receptor may associate with a G protein and, with ref. 66, was the first structure of a GPCR in an activated state.

    ADS  CAS  PubMed  Google Scholar 

  39. 39

    Lagerström, M. C. & Schiöth, H. B. Structural diversity of G protein-coupled receptors and significance for drug discovery. Nature Rev. Drug Discov. 7, 339–357 (2008)

    Google Scholar 

  40. 40

    Unal, H. & Karnik, S. S. Domain coupling in GPCRs: the engine for induced conformational changes. Trends Pharmacol. Sci. 33, 79–88 (2012)

    CAS  PubMed  Google Scholar 

  41. 41

    Hurst, D. P. et al. A lipid pathway for ligand binding is necessary for a cannabinoid G protein-coupled receptor. J. Biol. Chem. 285, 17954–17964 (2010)

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42

    Dror, R. O. et al. Pathway and mechanism of drug binding to G-protein-coupled receptors. Proc. Natl Acad. Sci. USA 108, 13118–13123 (2011)Long timescale molecular dynamics simulations are used to define a potential intermediate in the GPCR conformational change from the active to inactive state, and shows the potential for studying the activation mechanism of GPCR through molecular simulations.

    ADS  CAS  PubMed  Google Scholar 

  43. 43

    González, A., Perez-Acle, T., Pardo, L. & Deupi, X. Molecular basis of ligand dissociation in β-adrenergic receptors. PLoS ONE 6, e23815 (2011)

    ADS  PubMed  PubMed Central  Google Scholar 

  44. 44

    Ballesteros, J. A. & Weinstein, H. 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 (1995)

    CAS  Google Scholar 

  45. 45

    Madabushi, S. et al. Evolutionary trace of G protein-coupled receptors reveals clusters of residues that determine global and class-specific functions. J. Biol. Chem. 279, 8126–8132 (2004)

    CAS  PubMed  Google Scholar 

  46. 46

    Barth, P., Wallner, B. & Baker, D. Prediction of membrane protein structures with complex topologies using limited constraints. Proc. Natl Acad. Sci. USA 106, 1409–1414 (2009)

    ADS  CAS  PubMed  Google Scholar 

  47. 47

    Schlinkmann, K. M. et al. Critical features for biosynthesis, stability, and functionality of a G protein-coupled receptor uncovered by all-versus-all mutations. Proc. Natl Acad. Sci. USA 109, 9810–9815 (2012)

    ADS  CAS  PubMed  Google Scholar 

  48. 48

    Congreve, M., Langmead, C. J., Mason, J. S. & Marshall, F. H. Progress in structure based drug design for G protein-coupled receptors. J. Med. Chem. 54, 4283–4311 (2011)

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49

    Heitz, F. et al. Site-directed mutagenesis of the putative human muscarinic M2 receptor binding site. Eur. J. Pharmacol. 380, 183–195 (1999)

    CAS  PubMed  Google Scholar 

  50. 50

    Katritch, V., Cherezov, V. & Stevens, R. C. Diversity and modularity of G protein-coupled receptor structures. Trends Pharmacol. Sci. 33, 17–27 (2011)

    PubMed  PubMed Central  Google Scholar 

  51. 51

    Valiquette, M., Parent, S., Loisel, T. P. & Bouvier, M. Mutation of tyrosine-141 inhibits insulin-promoted tyrosine phosphorylation and increased responsiveness of the human β2-adrenergic receptor. EMBO J. 14, 5542–5549 (1995)

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52

    Jaakola, V. P., Prilusky, J., Sussman, J. L. & Goldman, A. G. Protein-coupled receptors show unusual patterns of intrinsic unfolding. Protein Eng. Des. Sel. 18, 103–110 (2005)

    CAS  PubMed  Google Scholar 

  53. 53

    Gsponer, J. & Babu, M. M. The rules of disorder or why disorder rules. Prog. Biophys. Mol. Biol. 99, 94–103 (2009)

    CAS  PubMed  Google Scholar 

  54. 54

    Babu, M. M., Kriwacki, R. W. & Pappu, R. V. Structural biology. Versatility from protein disorder. Science 337, 1460–1461 (2012)

    ADS  CAS  PubMed  Google Scholar 

  55. 55

    Qin, K., Dong, C., Wu, G. & Lambert, N. A. Inactive-state preassembly of Gq-coupled receptors and Gq heterotrimers. Nature Chem. Biol. 7, 740–747 (2011)

    CAS  Google Scholar 

  56. 56

    Nobles, K. N. et al. Distinct phosphorylation sites on the β2-adrenergic receptor establish a barcode that encodes differential functions of β-arrestin. Sci. Signal. 4, ra51 (2011)

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57

    Samama, P., Cotecchia, S., Costa, T. & Lefkowitz, R. J. A. Mutation-induced activated state of the β2-adrenergic receptor. Extending the ternary complex model. J. Biol. Chem. 268, 4625–4636 (1993)

    CAS  PubMed  Google Scholar 

  58. 58

    Deupi, X. & Standfuss, J. Structural insights into agonist-induced activation of G-protein-coupled receptors. Curr. Opin. Struct. Biol. 21, 541–551 (2011)

    CAS  PubMed  Google Scholar 

  59. 59

    Hofmann, K. P. et al. A G protein-coupled receptor at work: the rhodopsin model. Trends Biochem. Sci. 34, 540–552 (2009)

    CAS  PubMed  Google Scholar 

  60. 60

    Rosenbaum, D. M., Rasmussen, S. G. & Kobilka, B. K. The structure and function of G-protein-coupled receptors. Nature 459, 356–363 (2009)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  61. 61

    Bockenhauer, S., Furstenberg, A., Yao, X. J., Kobilka, B. K. & Moerner, W. E. Conformational dynamics of single G protein-coupled receptors in solution. J. Phys. Chem. B 115, 13328–13338 (2011)

    CAS  PubMed  PubMed Central  Google Scholar 

  62. 62

    Ghanouni, P. et al. Functionally different agonists induce distinct conformations in the G protein coupling domain of the β2 adrenergic receptor. J. Biol. Chem. 276, 24433–24436 (2001)

    CAS  PubMed  Google Scholar 

  63. 63

    Dror, R. O. et al. Activation mechanism of the β2-adrenergic receptor. Proc. Natl Acad. Sci. USA 108, 18684–18689 (2011)

    ADS  CAS  PubMed  Google Scholar 

  64. 64

    Kahsai, A. W. et al. Multiple ligand-specific conformations of the β2-adrenergic receptor. Nature Chem. Biol. 7, 692–700 (2011)

    CAS  Google Scholar 

  65. 65

    West, G. M. et al. Ligand-dependent perturbation of the conformational ensemble for the GPCR β2 adrenergic receptor revealed by HDX. Structure 19, 1424–1432 (2011)

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66

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

    ADS  CAS  PubMed  Google Scholar 

  67. 67

    Süel, G. M., Lockless, S. W., Wall, M. A. & Ranganathan, R. Evolutionarily conserved networks of residues mediate allosteric communication in proteins. Nature Struct. Biol. 10, 59–69 (2003)

    PubMed  Google Scholar 

  68. 68

    Vaidehi, N. & Kenakin, T. The role of conformational ensembles of seven transmembrane receptors in functional selectivity. Curr. Opin. Pharmacol. 10, 775–781 (2010)

    CAS  PubMed  Google Scholar 

  69. 69

    Provasi, D., Artacho, M. C., Negri, A., Mobarec, J. C. & Filizola, M. Ligand-induced modulation of the free-energy landscape of G protein-coupled receptors explored by adaptive biasing techniques. PLOS Comput. Biol. 7, e1002193 (2011)

    ADS  MathSciNet  CAS  PubMed  PubMed Central  Google Scholar 

  70. 70

    Wheatley, M. et al. Lifting the lid on GPCRs: the role of extracellular loops. Br. J. Pharmacol. 165, 1688–1703 (2012)

    CAS  PubMed  PubMed Central  Google Scholar 

  71. 71

    Ahuja, S. et al. Location of the retinal chromophore in the activated state of rhodopsin*. J. Biol. Chem. 284, 10190–10201 (2009)

    CAS  PubMed  PubMed Central  Google Scholar 

  72. 72

    Bokoch, M. P. et al. Ligand-specific regulation of the extracellular surface of a G-protein-coupled receptor. Nature 463, 108–112 (2010)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  73. 73

    Lebon, G., Warne, T. & Tate, C. G. Agonist-bound structures of G protein-coupled receptors. Curr. Opin. Struct. Biol. 22, 482–490 (2012)

    CAS  PubMed  Google Scholar 

  74. 74

    Deupi, X., Standfuss, J. & Schertler, G. Conserved activation pathways in G-protein-coupled receptors. Biochem. Soc. Trans. 40, 383–388 (2012)

    CAS  PubMed  Google Scholar 

  75. 75

    Sansuk, K. et al. A structural insight into the reorientation of transmembrane domains 3 and 5 during family a G protein-coupled receptor activation. Mol. Pharmacol. 79, 262–269 (2011)

    CAS  PubMed  Google Scholar 

  76. 76

    Farrens, D. L., Altenbach, C., Yang, K., Hubbell, W. L. & Khorana, H. G. Requirement of rigid-body motion of transmembrane helices for light activation of rhodopsin. Science 274, 768–770 (1996)

    ADS  CAS  PubMed  Google Scholar 

  77. 77

    Sheikh, S. P., Zvyaga, T. A., Lichtarge, O., Sakmar, T. P. & Bourne, H. R. Rhodopsin activation blocked by metal-ion-binding sites linking transmembrane helices C and F. Nature 383, 347–350 (1996)

    ADS  CAS  PubMed  Google Scholar 

  78. 78

    Altenbach, C., Kusnetzow, A. K., Ernst, O. P., Hofmann, K. P. & Hubbell, W. L. High-resolution distance mapping in rhodopsin reveals the pattern of helix movement due to activation. Proc. Natl Acad. Sci. USA 105, 7439–7444 (2008)

    ADS  CAS  PubMed  Google Scholar 

  79. 79

    Ye, S. et al. Tracking G-protein-coupled receptor activation using genetically encoded infrared probes. Nature 464, 1386–1389 (2010)

    ADS  CAS  PubMed  Google Scholar 

  80. 80

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

    CAS  PubMed  Google Scholar 

  81. 81

    Moukhametzianov, R. et al. Two distinct conformations of helix 6 observed in antagonist-bound structures of a β1-adrenergic receptor. Proc. Natl Acad. Sci. USA 108, 8228–8232 (2011)

    ADS  CAS  PubMed  Google Scholar 

  82. 82

    Chung, K. Y. et al. Conformational changes in the G protein Gs induced by the β2 adrenergic receptor. Nature 477, 611–615 (2011)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  83. 83

    Whorton, M. R. et al. A monomeric G protein-coupled receptor isolated in a high-density lipoprotein particle efficiently activates its G protein. Proc. Natl Acad. Sci. USA 104, 7682–7687 (2007)

    ADS  CAS  PubMed  Google Scholar 

  84. 84

    Rajagopal, S., Rajagopal, K. & Lefkowitz, R. J. Teaching old receptors new tricks: biasing seven-transmembrane receptors. Nature Rev. Drug Discov. 9, 373–386 (2010)

    CAS  Google Scholar 

  85. 85

    Kenakin, T. Collateral efficacy in drug discovery: taking advantage of the good (allosteric) nature of 7TM receptors. Trends Pharmacol. Sci. 28, 407–415 (2007)

    CAS  PubMed  Google Scholar 

  86. 86

    Rosenkilde, M. M., Benned-Jensen, T., Frimurer, T. M. & Schwartz, T. W. The minor binding pocket: a major player in 7TM receptor activation. Trends Pharmacol. Sci. 31, 567–574 (2010)

    CAS  PubMed  Google Scholar 

  87. 87

    Liu, J. J., Horst, R., Katritch, V., Stevens, R. C. & Wuthrich, K. Biased signaling pathways in β2-adrenergic receptor characterized by 19F-NMR. Science 335, 1106–1110 (2012)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  88. 88

    Rahmeh, R. et al. Structural insights into biased G protein-coupled receptor signaling revealed by fluorescence spectroscopy. Proc. Natl Acad. Sci. USA 109, 6733–6738 (2012)

    ADS  CAS  PubMed  Google Scholar 

  89. 89

    Parthier, C., Reedtz-Runge, S., Rudolph, R. & Stubbs, M. T. Passing the baton in class B GPCRs: peptide hormone activation via helix induction? Trends Biochem. Sci. 34, 303–310 (2009)

    CAS  PubMed  Google Scholar 

  90. 90

    Urwyler, S. Allosteric modulation of family C G-protein-coupled receptors: from molecular insights to therapeutic perspectives. Pharmacol. Rev. 63, 59–126 (2011)

    CAS  PubMed  Google Scholar 

  91. 91

    Araç, D. et al. A novel evolutionarily conserved domain of cell-adhesion GPCRs mediates autoproteolysis. EMBO J. 31, 1364–1378 (2012)

    PubMed  PubMed Central  Google Scholar 

  92. 92

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

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  93. 93

    Han, Y., Moreira, I. S., Urizar, E., Weinstein, H. & Javitch, J. A. Allosteric communication between protomers of dopamine class a GPCR dimers modulates activation. Nature Chem. Biol. 5, 688–695 (2009)

    CAS  Google Scholar 

  94. 94

    Congreve, M. et al. Discovery of 1,2,4-triazine derivatives as adenosine A2A antagonists using structure based drug design. J. Med. Chem. 55, 1898–1903 (2012)This paper describes the development of new preclinical compounds for the treatment of Parkinson’s disease by structure-based drug design, and shows structures of the lead compounds in the thermostabilized A 2A R previously developed, and the structure determined bound to inverse agonists12.

    CAS  PubMed  PubMed Central  Google Scholar 

  95. 95

    Heinis, C., Rutherford, T., Freund, S. & Winter, G. Phage-encoded combinatorial chemical libraries based on bicyclic peptides. Nature Chem. Biol. 5, 502–507 (2009)

    CAS  Google Scholar 

  96. 96

    Valant, C., Robert Lane, J., Sexton, P. M. & Christopoulos, A. The best of both worlds? Bitopic orthosteric/allosteric ligands of G protein-coupled receptors. Annu. Rev. Pharmacol. Toxicol. 52, 153–178 (2012)

    CAS  PubMed  Google Scholar 

  97. 97

    Herr, D. R. Potential use of G protein-coupled receptor-blocking monoclonal antibodies as therapeutic agents for cancers. Int. Rev. Cell Mol. Biol. 297, 45–81 (2012)

    CAS  PubMed  Google Scholar 

  98. 98

    Huber, T. & Sakmar, T. P. Escaping the flatlands: new approaches for studying the dynamic assembly and activation of GPCR signaling complexes. Trends Pharmacol. Sci. 32, 410–419 (2011)

    CAS  PubMed  PubMed Central  Google Scholar 

  99. 99

    Kiel, C. et al. Structural and functional protein network analyses predict novel signaling functions for rhodopsin. Mol. Syst. Biol. 7, 551 (2011)

    PubMed  PubMed Central  Google Scholar 

  100. 100

    Ahles, A., Rochais, F., Frambach, T., Bunemann, M. & Engelhardt, S. A. Polymorphism-specific “memory” mechanism in the β2-adrenergic receptor. Sci. Signal. 4, ra53 (2011)

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank A. Deonarine, C. Chothia, D. Ghosal, J. Marsh, J. Garcia-Nafria, K. R. Vinothkumar, R. Henderson, R. Hegde, S. Balaji, S. Chavali and T. Flock for their comments on this work. This work was supported by the UK Medical Research Council (U105185859), HFSP (RGY0073/2010; M.M.B.), the EMBO Young Investigator Program (M.M.B.), and ERASysBio+ (GRAPPLE; M.M.B.). A.J.V. acknowledges LMB Cambridge Scholarship and St. John’s College Benefactor Scholarship for financial support. G.L. was funded by Heptares Therapeutics, the UK Medical Research Council and by the CNRS and Agence Nationale de la Recherche (grant ANR-09-BLAN-0272). X.D. and G.F.S. acknowledge the Swiss National Science Foundation (grant 31003A_132815) and the ETH Zürich within the framework of the National Center for Competence in Research in Structural Biology Program for financial support. C.G.T. acknowledges the Medical Research Council Technology Development Gap Fund, Pfizer, and core funding from the UK Medical Research Council (U105197215). We apologize to our colleagues whose work was not cited owing to space limitations.

Author information

Affiliations

Authors

Contributions

A.J.V. and M.M.B. designed the study, analysed the results and wrote the manuscript. A.J.V. performed all calculations. X.D., G.L., C.G.T. and G.F.S. provided data, and contributed to the analysis and writing of the manuscript.

Corresponding authors

Correspondence to A. J. Venkatakrishnan or M. Madan Babu.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains suggestions for further reading, Supplementary Table 1 and Supplementary References. (PDF 260 kb)

Supplementary Data

This file contains Supplementary Table 2 which shows consensus inter-TM contact network of the GPCR fold and Supplementary Table 3 which shows topologically equivalent residues across the different GPCRs. (XLSX 106 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Venkatakrishnan, A., Deupi, X., Lebon, G. et al. Molecular signatures of G-protein-coupled receptors. Nature 494, 185–194 (2013). https://doi.org/10.1038/nature11896

Download citation

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing