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.

  • Review Article
  • Published:

Structure and dynamics of GPCR signaling complexes

Abstract

G-protein-coupled receptors (GPCRs) relay numerous extracellular signals by triggering intracellular signaling through coupling with G proteins and arrestins. Recent breakthroughs in the structural determination of GPCRs and GPCR–transducer complexes represent important steps toward deciphering GPCR signal transduction at a molecular level. A full understanding of the molecular basis of GPCR-mediated signaling requires elucidation of the dynamics of receptors and their transducer complexes as well as their energy landscapes and conformational transition rates. Here, we summarize current insights into the structural plasticity of GPCR–G-protein and GPCR–arrestin complexes that underlies the regulation of the receptor’s intracellular signaling profile.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Purchase on Springer Link

Instant access to full article PDF

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: G-protein-coupled receptor signal transduction.
Fig. 2: Receptor-mediated conformational changes in Gα.
Fig. 3: Conformational changes in arrestin-2 upon activation.
Fig. 4: Structure and interaction interface of the rhodopsin–arrestin-1 complex.

Similar content being viewed by others

References

  1. Kenakin, T. New concepts in pharmacological efficacy at 7TM receptors: IUPHAR review 2. Br. J. Pharmacol. 168, 554–575 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Zhang, D., Zhao, Q. & Wu, B. Structural studies of G protein-coupled receptors. Mol. Cells 38, 836–842 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Venkatakrishnan, A. J. et al. Diverse activation pathways in class A GPCRs converge near the G-protein-coupling region. Nature 536, 484–487 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Wu, F., Song, G., de Graaf, C. & Stevens, R. C. Structure and function of peptide-binding G protein-coupled receptors. J. Mol. Biol. 429, 2726–2745 (2017).

    Article  CAS  PubMed  Google Scholar 

  5. Shonberg, J., Kling, R. C., Gmeiner, P. & Löber, S. GPCR crystal structures: medicinal chemistry in the pocket. Bioorg. Med. Chem. 23, 3880–3906 (2015).

    Article  CAS  PubMed  Google Scholar 

  6. Manglik, A. & Kobilka, B. The role of protein dynamics in GPCR function: insights from the β2AR and rhodopsin. Curr. Opin. Cell Biol. 27, 136–143 (2014).

    Article  CAS  PubMed  Google Scholar 

  7. Latorraca, N. R., Venkatakrishnan, A. J. & Dror, R. O. GPCR dynamics: structures in motion. Chem. Rev. 117, 139–155 (2017).

    Article  CAS  PubMed  Google Scholar 

  8. Ye, L., Van Eps, N., Zimmer, M., Ernst, O. P. & Prosser, R. S. Activation of the A2A adenosine G-protein-coupled receptor by conformational selection. Nature 533, 265–268 (2016).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Okude, J. et al. Identification of a conformational equilibrium that determines the efficacy and functional selectivity of the μ-opioid receptor. Angew. Chem. Int. Edn Engl. 54, 15771–15776 (2015).

    Article  CAS  Google Scholar 

  11. Manglik, A. et al. Structural insights into the dynamic process of β2-adrenergic receptor signaling. Cell 161, 1101–1111 (2015). NMR spectroscopy and DEER spectroscopy studies revealed the structural heterogeneity and dynamic character of the β2 adrenergic receptor.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. DeVree, B. T. et al. Allosteric coupling from G protein to the agonist-binding pocket in GPCRs. Nature 535, 182–186 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Sounier, R. et al. Propagation of conformational changes during μ-opioid receptor activation. Nature 524, 375–378 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Rasmussen, S. G. F. et al. Crystal structure of the β2 adrenergic receptor-Gs protein complex. Nature 477, 549–555 (2011). This paper describes the first structure of a GPCR–G-protein complex, highlighting receptor-mediated conformational changes within the G protein that are important for nucleotide release.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Liang, Y.-L. et al. Phase-plate cryo-EM structure of a class B GPCR-G-protein complex. Nature 546, 118–123 (2017).

    Article  CAS  PubMed  Google Scholar 

  16. Carpenter, B., Nehmé, R., Warne, T., Leslie, A. G. W. & Tate, C. G. Structure of the adenosine A(2A) receptor bound to an engineered G protein. Nature 536, 104–107 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Zhang, Y. et al. Cryo-EM structure of the activated GLP-1 receptor in complex with a G protein. Nature 546, 248–253 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Zhou, X. E. et al. Identification of phosphorylation codes for arrestin recruitment by G protein-coupled receptors. Cell 170, 457–469.e13 (2017).This paper describes the first high-resolution structure of a GPCR–arrestin complex and explores the role of receptor C-tail phosphate patterns in arrestin binding affinity.

    Article  CAS  PubMed  Google Scholar 

  20. Komolov, K. E. & Benovic, J. L. G protein-coupled receptor kinases: Past, present and future. Cell. Signal.  https://doi.org/10.1016/j.cellsig.2017.07.004 (2017). 

    PubMed  Google Scholar 

  21. Downes, G. B. & Gautam, N. The G protein subunit gene families. Genomics 62, 544–552 (1999).

    Article  CAS  PubMed  Google Scholar 

  22. Simon, M. I., Strathmann, M. P. & Gautam, N. Diversity of G proteins in signal transduction. Science 252, 802–808 (1991).

    Article  CAS  PubMed  Google Scholar 

  23. Higashijima, T., Ferguson, K. M., Sternweis, P. C., Smigel, M. D. & Gilman, A. G. Effects of Mg2+ and the beta gamma-subunit complex on the interactions of guanine nucleotides with G proteins. J. Biol. Chem. 262, 762–766 (1987).

    CAS  PubMed  Google Scholar 

  24. Kristiansen, K. Molecular mechanisms of ligand binding, signaling, and regulation within the superfamily of G-protein-coupled receptors: molecular modeling and mutagenesis approaches to receptor structure and function. Pharmacol. Ther. 103, 21–80 (2004).

    Article  CAS  PubMed  Google Scholar 

  25. Milligan, G. & Kostenis, E. Heterotrimeric G-proteins: a short history. Br. J. Pharmacol. 147, S46–S55 (2006). Suppl 1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Smrcka, A. V. G protein βγ subunits: central mediators of G protein-coupled receptor signaling. Cell. Mol. Life Sci. 65, 2191–2214 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Khan, S. M. et al. The expanding roles of Gβγ subunits in G protein-coupled receptor signaling and drug action. Pharmacol. Rev. 65, 545–577 (2013).

    Article  CAS  PubMed  Google Scholar 

  28. Ross, E. M. & Wilkie, T. M. GTPase-activating proteins for heterotrimeric G proteins: regulators of G protein signaling (RGS) and RGS-like proteins. Annu. Rev. Biochem. 69, 795–827 (2000).

    Article  CAS  PubMed  Google Scholar 

  29. Kimple, A. J., Bosch, D. E., Giguère, P. M. & Siderovski, D. P. Regulators of G-protein signaling and their Gα substrates: promises and challenges in their use as drug discovery targets. Pharmacol. Rev. 63, 728–749 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Oldham, W. M. & Hamm, H. E. Structural basis of function in heterotrimeric G proteins. Q. Rev. Biophys. 39, 117–166 (2006).

    Article  CAS  PubMed  Google Scholar 

  31. Sprang, S. R. G protein mechanisms: insights from structural analysis. Annu. Rev. Biochem. 66, 639–678 (1997).

    Article  CAS  PubMed  Google Scholar 

  32. Noel, J. P., Hamm, H. E. & Sigler, P. B. The 2.2 Å crystal structure of transducin-alpha complexed with GTP gamma S. Nature 366, 654–663 (1993).

    Article  CAS  PubMed  Google Scholar 

  33. Van Eps, N. et al. Interaction of a G protein with an activated receptor opens the interdomain interface in the alpha subunit. Proc. Natl. Acad. Sci. USA 108, 9420–9424 (2011). In this paper, DEER distance measurements are used to demonstrate that G-protein coupling to an activated receptor induces domain separation of the AHD and the Ras domain that opens up an exit pathway for GDP.

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Gao, Y. et al. Isolation and structure-function characterization of a signaling-active rhodopsin-G protein complex. J. Biol. Chem. 292, 14280–14289 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Grishina, G. & Berlot, C. H. A surface-exposed region of G in which substitutions decrease receptor-mediated activation and increase receptor affinity. Mol. Pharmacol. 57, 1081–1092 (2000).

    CAS  PubMed  Google Scholar 

  37. Warner, D. R. & Weinstein, L. S. A mutation in the heterotrimeric stimulatory guanine nucleotide binding protein α-subunit with impaired receptor-mediated activation because of elevated GTPase activity. Proc. Natl. Acad. Sci. USA 96, 4268–4272 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Yao, X.-Q. et al. Dynamic coupling and allosteric networks in the α subunit of heterotrimeric G proteins. J. Biol. Chem. 291, 4742–4753 (2016).

    Article  CAS  PubMed  Google Scholar 

  39. Ceruso, M. A., Periole, X. & Weinstein, H. Molecular dynamics simulations of transducin: interdomain and front to back communication in activation and nucleotide exchange. J. Mol. Biol. 338, 469–481 (2004).

    Article  CAS  PubMed  Google Scholar 

  40. Dror, R. O. et al. Structural basis for nucleotide exchange in heterotrimeric G proteins. Science 348, 1361–1365 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Markby, D. W., Onrust, R. & Bourne, H. R. Separate GTP binding and GTPase activating domains of a G alpha subunit. Science 262, 1895–1901 (1993). This elegant paper demonstrates that the AHD specific for heterotrimeric G proteins shows GTPase-activating protein (GAP) activity.

    Article  CAS  PubMed  Google Scholar 

  42. Aris, L. et al. Structural requirements for the stabilization of metarhodopsin II by the C terminus of the α subunit of transducin. J. Biol. Chem. 276, 2333–2339 (2001).

    Article  CAS  PubMed  Google Scholar 

  43. Schwindinger, W. F., Miric, A., Zimmerman, D. & Levine, M. A. A novel Gs alpha mutant in a patient with Albright hereditary osteodystrophy uncouples cell surface receptors from adenylyl cyclase. J. Biol. Chem. 269, 25387–25391 (1994).

    CAS  PubMed  Google Scholar 

  44. Sullivan, K. A. et al. Identification of receptor contact site involved in receptor-G protein coupling. Nature 330, 758–760 (1987).

    Article  CAS  PubMed  Google Scholar 

  45. Oldham, W. M., Van Eps, N., Preininger, A. M., Hubbell, W. L. & Hamm, H. E. Mechanism of the receptor-catalyzed activation of heterotrimeric G proteins. Nat. Struct. Mol. Biol. 13, 772–777 (2006).

    Article  CAS  PubMed  Google Scholar 

  46. Conklin, B. R., Farfel, Z., Lustig, K. D., Julius, D. & Bourne, H. R. Substitution of three amino acids switches receptor specificity of Gq α to that of Gi α. Nature 363, 274–276 (1993).

    Article  CAS  PubMed  Google Scholar 

  47. Herrmann, R. et al. Rhodopsin-transducin coupling: role of the Galpha C-terminus in nucleotide exchange catalysis. Vision Res. 46, 4582–4593 (2006). This study describes the important role of the αN–β1 hinge region for rhodopsin-mediated nucleotide release in engaged cognate Gprotein transducin.

    Article  CAS  PubMed  Google Scholar 

  48. Iiri, T., Herzmark, P., Nakamoto, J. M., van Dop, C. & Bourne, H. R. Rapid GDP release from Gs α in patients with gain and loss of endocrine function. Nature 371, 164–168 (1994).

    Article  CAS  PubMed  Google Scholar 

  49. Posner, B. A., Mixon, M. B., Wall, M. A., Sprang, S. R. & Gilman, A. G. The A326S mutant of Gialpha1 as an approximation of the receptor-bound state. J. Biol. Chem. 273, 21752–21758 (1998).

    Article  CAS  PubMed  Google Scholar 

  50. Thomas, T. C., Schmidt, C. J. & Neer, E. J. G-protein alpha o subunit: mutation of conserved cysteines identifies a subunit contact surface and alters GDP affinity. Proc. Natl. Acad. Sci. USA 90, 10295–10299 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Sun, D. et al. Probing Gαi1 protein activation at single-amino acid resolution. Nat. Struct. Mol. Biol. 22, 686–694 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Kaya, A. I. et al. A conserved hydrophobic core in Gαi1 regulates G protein activation and release from activated receptor. J. Biol. Chem. 291, 19674–19686 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Kaya, A. I. et al. A conserved phenylalanine as a relay between the α5 helix and the GDP binding region of heterotrimeric Gi protein α subunit. J. Biol. Chem. 289, 24475–24487 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Flock, T. et al. Universal allosteric mechanism for Gα activation by GPCRs. Nature 524, 173–179 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Alexander, N. S. et al. Energetic analysis of the rhodopsin-G-protein complex links the α5 helix to GDP release. Nat. Struct. Mol. Biol. 21, 56–63 (2014).

    Article  CAS  PubMed  Google Scholar 

  56. Herrmann, R., Heck, M., Henklein, P., Hofmann, K. P. & Ernst, O. P. Signal transfer from GPCRs to G proteins: role of the G alpha N-terminal region in rhodopsin-transducin coupling. J. Biol. Chem. 281, 30234–30241 (2006).

    Article  CAS  PubMed  Google Scholar 

  57. Franke, R. R., König, B., Sakmar, T. P., Khorana, H. G. & Hofmann, K. P. Rhodopsin mutants that bind but fail to activate transducin. Science 250, 123–125 (1990).

    Article  CAS  PubMed  Google Scholar 

  58. Muradov, K. G. & Artemyev, N. O. Coupling between the N- and C-terminal domains influences transducin-α intrinsic GDP/GTP exchange. Biochemistry 39, 3937–3942 (2000).

    Article  CAS  PubMed  Google Scholar 

  59. Zhang, Q., Okamura, M., Guo, Z.-D., Niwa, S. & Haga, T. Effects of partial agonists and Mg2+ ions on the interaction of M2 muscarinic acetylcholine receptor and G protein Galpha i1 subunit in the M2-Galpha i1 fusion protein. J. Biochem. 135, 589–596 (2004).

    Article  CAS  PubMed  Google Scholar 

  60. Seifert, R., Gether, U., Wenzel-Seifert, K. & Kobilka, B. K. Effects of guanine, inosine, and xanthine nucleotides on β(2)-adrenergic receptor/G(s) interactions: evidence for multiple receptor conformations. Mol. Pharmacol. 56, 348–358 (1999).

    Article  CAS  PubMed  Google Scholar 

  61. Selley, D. E., Sim, L. J., Xiao, R., Liu, Q. & Childers, S. R. mu-Opioid receptor-stimulated guanosine-5′-O-(gamma-thio)-triphosphate binding in rat thalamus and cultured cell lines: signal transduction mechanisms underlying agonist efficacy. Mol. Pharmacol. 51, 87–96 (1997).

    Article  CAS  PubMed  Google Scholar 

  62. Roberts, D. J., Lin, H. & Strange, P. G. Mechanisms of agonist action at D2 dopamine receptors. Mol. Pharmacol. 66, 1573–1579 (2004).

    Article  CAS  PubMed  Google Scholar 

  63. Gregorio, G. G. et al. Single-molecule analysis of ligand efficacy in β2AR-G-protein activation. Nature 547, 68–73 (2017). This study provides single-molecule insights into ligand-dependent allosteric regulation between the orthosteric binding site of the receptor and the nucleotide-binding pocket of the engaged G protein.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Harrison, C. & Traynor, J. R. The [35S]GTPgammaS binding assay: approaches and applications in pharmacology. Life Sci. 74, 489–508 (2003).

    Article  CAS  PubMed  Google Scholar 

  65. Toyama, Y. et al. Dynamic regulation of GDP binding to G proteins revealed by magnetic field-dependent NMR relaxation analyses. Nat. Commun. 8, 14523 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Goricanec, D. et al. Conformational dynamics of a G-protein α subunit is tightly regulated by nucleotide binding. Proc. Natl. Acad. Sci. USA 113, E3629–E3638 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Abdulaev, N. G. et al. The receptor-bound “empty pocket” state of the heterotrimeric G-protein alpha-subunit is conformationally dynamic. Biochemistry 45, 12986–12997 (2006).

    Article  CAS  PubMed  Google Scholar 

  68. Furness, S. G. B. et al. Ligand-dependent modulation of G protein conformation alters drug efficacy. Cell 167, 739–749.e11 (2016). This article describes ligand-dependent conformational differences in the calcitonin-receptor-coupled G protein that can modulate the GTP sensitivity of the ternary complex.

    Article  CAS  PubMed  Google Scholar 

  69. DeWire, S. M., Ahn, S., Lefkowitz, R. J. & Shenoy, S. K. β-arrestins and cell signaling. Annu. Rev. Physiol. 69, 483–510 (2007).

    Article  CAS  PubMed  Google Scholar 

  70. Nobles, K. N., Guan, Z., Xiao, K., Oas, T. G. & Lefkowitz, R. J. The active conformation of β-arrestin1: direct evidence for the phosphate sensor in the N-domain and conformational differences in the active states of β-arrestins1 and -2. J. Biol. Chem. 282, 21370–21381 (2007).

    Article  CAS  PubMed  Google Scholar 

  71. Gurevich, V. V. & Gurevich, E. V. Overview of different mechanisms of arrestin‐mediated signaling. Curr. Protoc. Pharmacol. 67, 2.10.1–2.10.9 (2014).

    Article  Google Scholar 

  72. Peterson, Y. K. & Luttrell, L. M. The diverse roles of arrestin scaffolds in G protein-coupled receptor signaling. Pharmacol. Rev. 69, 256–297 (2017).

    Article  PubMed  Google Scholar 

  73. Kohout, T. A., Lin, F. S., Perry, S. J., Conner, D. A. & Lefkowitz, R. J. beta-Arrestin 1 and 2 differentially regulate heptahelical receptor signaling and trafficking. Proc. Natl. Acad. Sci. USA 98, 1601–1606 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Gurevich, E. V., Benovic, J. L. & Gurevich, V. V. Arrestin2 and arrestin3 are differentially expressed in the rat brain during postnatal development. Neuroscience 109, 421–436 (2002).

    Article  CAS  PubMed  Google Scholar 

  75. Gurevich, E. V., Benovic, J. L. & Gurevich, V. V. Arrestin2 expression selectively increases during neural differentiation. J. Neurochem 91, 1404–1416 (2004).

    Article  CAS  PubMed  Google Scholar 

  76. Scott, M. G. H. et al. Differential nucleocytoplasmic shuttling of β-arrestins. Characterization of a leucine-rich nuclear export signal in β-arrestin2. J. Biol. Chem. 277, 37693–37701 (2002).

    Article  CAS  PubMed  Google Scholar 

  77. Oakley, R. H., Laporte, S. A., Holt, J. A., Caron, M. G. & Barak, L. S. Differential affinities of visual arrestin, beta arrestin1, and beta arrestin2 for G protein-coupled receptors delineate two major classes of receptors. J. Biol. Chem. 275, 17201–17210 (2000).

    Article  CAS  PubMed  Google Scholar 

  78. Srivastava, A., Gupta, B., Gupta, C. & Shukla, A. K. Emerging functional divergence of β-arrestin isoforms in GPCR function. Trends Endocrinol. Metab. 26, 628–642 (2015).

    Article  CAS  PubMed  Google Scholar 

  79. Hirsch, J. A., Schubert, C., Gurevich, V. V. & Sigler, P. B. The 2.8 A crystal structure of visual arrestin: a model for arrestin’s regulation. Cell 97, 257–269 (1999).

    Article  CAS  PubMed  Google Scholar 

  80. Han, M., Gurevich, V. V., Vishnivetskiy, S. A., Sigler, P. B. & Schubert, C. Crystal structure of β-arrestin at 1.9 A: possible mechanism of receptor binding and membrane translocation. Structure 9, 869–880 (2001).

    Article  CAS  PubMed  Google Scholar 

  81. Zhan, X., Gimenez, L. E., Gurevich, V. V. & Spiller, B. W. Crystal structure of arrestin-3 reveals the basis of the difference in receptor binding between two non-visual subtypes. J. Mol. Biol. 406, 467–478 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Sutton, R. B. et al. Crystal structure of cone arrestin at 2.3A: evolution of receptor specificity. J. Mol. Biol. 354, 1069–1080 (2005).

    Article  CAS  PubMed  Google Scholar 

  83. Gurevich, V. V. & Gurevich, E. V. Structural determinants of arrestin functions. Prog. Mol. Biol. Transl. Sci. 118, 57–92 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Granzin, J., Stadler, A., Cousin, A., Schlesinger, R. & Batra-Safferling, R. Structural evidence for the role of polar core residue Arg175 in arrestin activation. Sci. Rep. 5, 15808 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Kim, Y. J. et al. Crystal structure of pre-activated arrestin p44. Nature 497, 142–146 (2013).

    Article  CAS  PubMed  Google Scholar 

  86. Shukla, A. K. et al. Structure of active β-arrestin-1 bound to a G-protein-coupled receptor phosphopeptide. Nature 497, 137–141 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Shukla, A. K. et al. Visualization of arrestin recruitment by a G-protein-coupled receptor. Nature 512, 218–222 (2014). This study provides direct evidence by single-particle EM for the existence of two binding modes between arrestin and receptor.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Chen, Q. et al. Structural basis of arrestin-3 activation and signaling. Nat. Commun. 8, 1427 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  89. Ostermaier, M. K., Peterhans, C., Jaussi, R., Deupi, X. & Standfuss, J. Functional map of arrestin-1 at single amino acid resolution. Proc. Natl. Acad. Sci. USA 111, 1825–1830 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Lally, C. C. M., Bauer, B., Selent, J. & Sommer, M. E. C-edge loops of arrestin function as a membrane anchor. Nat Commun. 8, 14258 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Scheerer, P. & Sommer, M. E. Structural mechanism of arrestin activation. Curr. Opin. Struct. Biol. 45, 160–169 (2017).

    Article  CAS  PubMed  Google Scholar 

  92. Gimenez, L. E., Vishnivetskiy, S. A., Baameur, F. & Gurevich, V. V. Manipulation of very few receptor discriminator residues greatly enhances receptor specificity of non-visual arrestins. J. Biol. Chem. 287, 29495–29505 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Peterson, S. M. et al. Elucidation of G-protein and β-arrestin functional selectivity at the dopamine D2 receptor. Proc. Natl. Acad. Sci. USA 112, 7097–7102 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Prokop, S. et al. Differential manipulation of arrestin-3 binding to basal and agonist-activated G protein-coupled receptors. Cell. Signal. 36, 98–107 (2017).

    Article  CAS  PubMed  Google Scholar 

  95. Hanson, S. M. et al. Differential interaction of spin-labeled arrestin with inactive and active phosphorhodopsin. Proc. Natl. Acad. Sci. USA 103, 4900–4905 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Charest, P. G., Terrillon, S. & Bouvier, M. Monitoring agonist-promoted conformational changes of beta-arrestin in living cells by intramolecular BRET. EMBO Rep. 6, 334–340 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Shukla, A. K. et al. Distinct conformational changes in beta-arrestin report biased agonism at seven-transmembrane receptors. Proc. Natl. Acad. Sci. USA 105, 9988–9993 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Nuber, S. et al. β-Arrestin biosensors reveal a rapid, receptor-dependent activation/deactivation cycle. Nature 531, 661–664 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Lee, M.-H. et al. The conformational signature of β-arrestin2 predicts its trafficking and signalling functions. Nature 531, 665–668 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Kim, M. et al. Conformation of receptor-bound visual arrestin. Proc. Natl. Acad. Sci. USA 109, 18407–18412 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Zhuo, Y., Vishnivetskiy, S. A., Zhan, X., Gurevich, V. V. & Klug, C. S. Identification of receptor binding-induced conformational changes in non-visual arrestins. J. Biol. Chem. 289, 20991–21002 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Kirchberg, K. et al. Conformational dynamics of helix 8 in the GPCR rhodopsin controls arrestin activation in the desensitization process. Proc. Natl. Acad. Sci. USA 108, 18690–18695 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Sommer, M. E., Hofmann, K. P. & Heck, M. Distinct loops in arrestin differentially regulate ligand binding within the GPCR opsin. Nat. Commun. 3, 995 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  104. Zhuang, T. et al. Involvement of distinct arrestin-1 elements in binding to different functional forms of rhodopsin. Proc. Natl. Acad. Sci. USA 110, 942–947 (2013).

    Article  CAS  PubMed  Google Scholar 

  105. Tobin, A. B., Butcher, A. J. & Kong, K. C. Location, location, location...site-specific GPCR phosphorylation offers a mechanism for cell-type-specific signalling. Trends Pharmacol. Sci. 29, 413–420 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Butcher, A. J. et al. Differential G-protein-coupled receptor phosphorylation provides evidence for a signaling bar code. J. Biol. Chem. 286, 11506–11518 (2011).

    Article  CAS  PubMed  Google Scholar 

  107. Nobles, K. N. et al. Distinct phosphorylation sites on the β(2)-adrenergic receptor establish a barcode that encodes differential functions of β-arrestin. Sci. Signal. 4, ra51 (2011). The authors identify distinct phosphorylation patterns caused by distinct GRK isoforms and couple them to distinct arrestin BRET responses and signaling outcomes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Inagaki, S. et al. G protein-coupled receptor kinase 2 (GRK2) and 5 (GRK5) exhibit selective phosphorylation of the neurotensin receptor in vitro. Biochemistry 54, 4320–4329 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Ren, X.-R. et al. Different G protein-coupled receptor kinases govern G protein and beta-arrestin-mediated signaling of V2 vasopressin receptor. Proc. Natl. Acad. Sci. USA 102, 1448–1453 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Bouzo-Lorenzo, M. et al. Distinct phosphorylation sites on the ghrelin receptor, GHSR1a, establish a code that determines the functions of ß-arrestins. Sci. Rep. 6, 22495 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Prihandoko, R. et al. Distinct phosphorylation clusters determine the signaling outcome of free fatty acid receptor 4/G protein-coupled Receptor 120. Mol. Pharmacol. 89, 505–520 (2016).

    Article  CAS  PubMed  Google Scholar 

  112. Mendez, A. et al. Rapid and reproducible deactivation of rhodopsin requires multiple phosphorylation sites. Neuron 28, 153–164 (2000).

    Article  CAS  PubMed  Google Scholar 

  113. Vishnivetskiy, S. A. et al. Regulation of arrestin binding by rhodopsin phosphorylation level. J. Biol. Chem. 282, 32075–32083 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Yang, F. et al. Phospho-selective mechanisms of arrestin conformations and functions revealed by unnatural amino acid incorporation and (19)F-NMR. Nat. Commun. 6, 8202 (2015). An elegant study that reveals how distinct receptor C-tail phosphorylation patterns imprint specific arrestin conformations and dynamics.

    Article  PubMed  PubMed Central  Google Scholar 

  115. Gurevich, V. V. & Benovic, J. L. Visual arrestin interaction with rhodopsin. Sequential multisite binding ensures strict selectivity toward light-activated phosphorylated rhodopsin. J. Biol. Chem 268, 11628–11638 (1993).

    CAS  PubMed  Google Scholar 

  116. Kumari, P. et al. Core engagement with β-arrestin is dispensable for agonist-induced vasopressin receptor endocytosis and ERK activation. Mol. Biol. Cell 28, 1003–1010 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Cahill, T. J. III et al. Distinct conformations of GPCR-β-arrestin complexes mediate desensitization, signaling, and endocytosis. Proc. Natl. Acad. Sci. USA 114, 2562–2567 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  118. Kumari, P. et al. Functional competence of a partially engaged GPCR-β-arrestin complex. Nat. Commun. 7, 13416 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Jung, S.-R., Kushmerick, C., Seo, J. B., Koh, D.-S. & Hille, B. Muscarinic receptor regulates extracellular signal regulated kinase by two modes of arrestin binding. Proc. Natl. Acad. Sci. USA 114, E5579–E5588 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Peterhans, C., Lally, C. C. M., Ostermaier, M. K., Sommer, M. E. & Standfuss, J. Functional map of arrestin binding to phosphorylated opsin, with and without agonist. Sci. Rep. 6, 28686 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Richardson, M. D. et al. Human substance P receptor lacking the C-terminal domain remains competent to desensitize and internalize. J. Neurochem. 84, 854–863 (2003).

    Article  CAS  PubMed  Google Scholar 

  122. Jala, V. R., Shao, W.-H. & Haribabu, B. Phosphorylation-independent beta-arrestin translocation and internalization of leukotriene B4 receptors. J. Biol. Chem. 280, 4880–4887 (2005).

    Article  CAS  PubMed  Google Scholar 

  123. Granzin, J. et al. Crystal structure of p44, a constitutively active splice variant of visual arrestin. J. Mol. Biol. 416, 611–618 (2012).

    Article  CAS  PubMed  Google Scholar 

  124. Eichel, K., Jullié, D. & von Zastrow, M. β-Arrestin drives MAP kinase signalling from clathrin-coated structures after GPCR dissociation. Nat. Cell Biol. 18, 303–310 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors thank N. R. Latorraca for critical reading of the manuscript and insightful suggestions. This work was supported by National Institutes of Health grants R01NS028471 and R01GM083118 (B.K.K.), the German Academic Exchange Service (DAAD) (D.H.) and the American Heart Association Postdoctoral fellowship (17POST33410958) (M.M.). B.K.K. is supported by the Chan Zuckerberg Biohub.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Brian K. Kobilka.

Ethics declarations

Competing interests

B.K.K. is a cofounder and consultant for ConfometRx, Inc.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hilger, D., Masureel, M. & Kobilka, B.K. Structure and dynamics of GPCR signaling complexes. Nat Struct Mol Biol 25, 4–12 (2018). https://doi.org/10.1038/s41594-017-0011-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41594-017-0011-7

This article is cited by

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