Conformational Transitions and the Activation of Heterotrimeric G Proteins by G Protein-Coupled Receptors

Overview

Journal ACS Pharmacol Transl Sci

Publisher American Chemical Society

Specialty Biochemistry

Date 2020 Apr 8

PMID 32259062

Citations 9

Authors

Christopher Draper-Joyce

Sebastian George Barton Furness

Affiliations

Soon will be listed here.

Abstract

G protein-coupled receptors (GPCRs) are particularly attractive targets for therapeutic pharmaceuticals. This is because they are involved in almost all facets of physiology, in many pathophysiological processes, they are tractable due to their cell surface location, and can exhibit highly textured pharmacology. While the development of new drugs does not require the molecular details of the mechanism of activity for a particular target, there has been increasing interest in the GPCR field in these details. In part, this has come with the recognition that differential activity at a particular target might be a way in which to leverage drug activity, either through manipulation of efficacy or through differential coupling (signaling bias). To this end, the past few years have seen a number of publications that have specifically attempted to address one or more aspects of the molecular reaction pathway, leading to activation of heterotrimeric G proteins by GPCRs.

Citing Articles

Role of RGS17 in cisplatin-induced cochlear inflammation and ototoxicity via caspase-3 activation.

Al Aameri R, Alanisi E, Al Sallami D, Alberts I, Tischkau S, Rybak L Front Immunol. 2025; 16:1470625.

PMID: 40061942 PMC: 11885124. DOI: 10.3389/fimmu.2025.1470625.

Binding kinetics drive G protein subtype selectivity at the β-adrenergic receptor.

Jones A, Harman T, Harris M, Lewis O, Ladds G, Nietlispach D Nat Commun. 2024; 15(1):1334.

PMID: 38351103 PMC: 10864275. DOI: 10.1038/s41467-024-45680-7.

Protein conformational ensembles in function: roles and mechanisms.

Nussinov R, Liu Y, Zhang W, Jang H RSC Chem Biol. 2023; 4(11):850-864.

PMID: 37920394 PMC: 10619138. DOI: 10.1039/d3cb00114h.

Profiling of basal and ligand-dependent GPCR activities by means of a polyvalent cell-based high-throughput platform.

Zeghal M, Laroche G, Freitas J, Wang R, Giguere P Nat Commun. 2023; 14(1):3684.

PMID: 37407564 PMC: 10322906. DOI: 10.1038/s41467-023-39132-x.

Allosteric modulation of gonadotropin receptors.

Lazzaretti C, Simoni M, Casarini L, Paradiso E Front Endocrinol (Lausanne). 2023; 14:1179079.

PMID: 37305033 PMC: 10248450. DOI: 10.3389/fendo.2023.1179079.

References

Heck M, Hofmann K . Maximal rate and nucleotide dependence of rhodopsin-catalyzed transducin activation: initial rate analysis based on a double displacement mechanism. J Biol Chem. 2000; 276(13):10000-9. DOI: 10.1074/jbc.M009475200. View

Liang Y, Khoshouei M, Radjainia M, Zhang Y, Glukhova A, Tarrasch J . Phase-plate cryo-EM structure of a class B GPCR-G-protein complex. Nature. 2017; 546(7656):118-123. PMC: 5832441. DOI: 10.1038/nature22327. View

Flock T, Ravarani C, Sun D, Venkatakrishnan A, Kayikci M, Tate C . Universal allosteric mechanism for Gα activation by GPCRs. Nature. 2015; 524(7564):173-179. PMC: 4866443. DOI: 10.1038/nature14663. View

Rasmussen S, Choi H, Fung J, Pardon E, Casarosa P, Chae P . Structure of a nanobody-stabilized active state of the β(2) adrenoceptor. Nature. 2011; 469(7329):175-80. PMC: 3058308. DOI: 10.1038/nature09648. View

Gupte T, Malik R, Sommese R, Ritt M, Sivaramakrishnan S . Priming GPCR signaling through the synergistic effect of two G proteins. Proc Natl Acad Sci U S A. 2017; 114(14):3756-3761. PMC: 5389285. DOI: 10.1073/pnas.1617232114. View

Lambright D, Sondek J, Bohm A, Skiba N, Hamm H, SIGLER P . The 2.0 A crystal structure of a heterotrimeric G protein. Nature. 1996; 379(6563):311-9. DOI: 10.1038/379311a0. View

Sunahara R, Tesmer J, GILMAN A, Sprang S . Crystal structure of the adenylyl cyclase activator Gsalpha. Science. 1998; 278(5345):1943-7. DOI: 10.1126/science.278.5345.1943. View

Sun X, Singh S, Blumer K, Bowman G . Simulation of spontaneous G protein activation reveals a new intermediate driving GDP unbinding. Elife. 2018; 7. PMC: 6224197. DOI: 10.7554/eLife.38465. View

Kofuku Y, Ueda T, Okude J, Shiraishi Y, Kondo K, Maeda M . Efficacy of the β₂-adrenergic receptor is determined by conformational equilibrium in the transmembrane region. Nat Commun. 2012; 3:1045. PMC: 3658005. DOI: 10.1038/ncomms2046. View

10.

Glukhova A, Draper-Joyce C, Sunahara R, Christopoulos A, Wootten D, Sexton P . Rules of Engagement: GPCRs and G Proteins. ACS Pharmacol Transl Sci. 2020; 1(2):73-83. PMC: 7089011. DOI: 10.1021/acsptsci.8b00026. View

11.

Mixon M, Lee E, Coleman D, Berghuis A, GILMAN A, Sprang S . Tertiary and quaternary structural changes in Gi alpha 1 induced by GTP hydrolysis. Science. 1995; 270(5238):954-60. DOI: 10.1126/science.270.5238.954. View

12.

Kato H, Zhang Y, Hu H, Suomivuori C, Ngako Kadji F, Aoki J . Conformational transitions of a neurotensin receptor 1-G complex. Nature. 2019; 572(7767):80-85. PMC: 7065593. DOI: 10.1038/s41586-019-1337-6. View

13.

Maeda S, Qu Q, Robertson M, Skiniotis G, Kobilka B . Structures of the M1 and M2 muscarinic acetylcholine receptor/G-protein complexes. Science. 2019; 364(6440):552-557. PMC: 7034192. DOI: 10.1126/science.aaw5188. View

14.

Nygaard R, Zou Y, Dror R, Mildorf T, Arlow D, Manglik A . The dynamic process of β(2)-adrenergic receptor activation. Cell. 2013; 152(3):532-42. PMC: 3586676. DOI: 10.1016/j.cell.2013.01.008. View

15.

Wall M, Coleman D, Lee E, Posner B, GILMAN A, Sprang S . The structure of the G protein heterotrimer Gi alpha 1 beta 1 gamma 2. Cell. 1995; 83(6):1047-58. DOI: 10.1016/0092-8674(95)90220-1. View

16.

Schafer C, Fay J, Janz J, Farrens D . Decay of an active GPCR: Conformational dynamics govern agonist rebinding and persistence of an active, yet empty, receptor state. Proc Natl Acad Sci U S A. 2016; 113(42):11961-11966. PMC: 5081659. DOI: 10.1073/pnas.1606347113. View

17.

Mary S, Damian M, Louet M, Floquet N, Fehrentz J, Marie J . Ligands and signaling proteins govern the conformational landscape explored by a G protein-coupled receptor. Proc Natl Acad Sci U S A. 2012; 109(21):8304-9. PMC: 3361445. DOI: 10.1073/pnas.1119881109. View

18.

Gregorio G, Masureel M, Hilger D, Terry D, Juette M, Zhao H . Single-molecule analysis of ligand efficacy in βAR-G-protein activation. Nature. 2017; 547(7661):68-73. PMC: 5502743. DOI: 10.1038/nature22354. View

19.

De Lean A, Stadel J, Lefkowitz R . A ternary complex model explains the agonist-specific binding properties of the adenylate cyclase-coupled beta-adrenergic receptor. J Biol Chem. 1980; 255(15):7108-17. View

20.

Van Eps N, Caro L, Morizumi T, Kusnetzow A, Szczepek M, Hofmann K . Conformational equilibria of light-activated rhodopsin in nanodiscs. Proc Natl Acad Sci U S A. 2017; 114(16):E3268-E3275. PMC: 5402410. DOI: 10.1073/pnas.1620405114. View