Mechanistic insights into GPCR-G protein interactions.

Autor: Mahoney JP; Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI 48109, United States., Sunahara RK; Department of Pharmacology, University of California at San Diego, La Jolla, CA 92093, United States. Electronic address: rsunahara@ucsd.edu.
Jazyk: angličtina
Zdroj: Current opinion in structural biology [Curr Opin Struct Biol] 2016 Dec; Vol. 41, pp. 247-254. Date of Electronic Publication: 2016 Nov 18.
DOI: 10.1016/j.sbi.2016.11.005
Abstrakt: G protein-coupled receptors (GPCRs) respond to extracellular stimuli and interact with several intracellular binding partners to elicit cellular responses, including heterotrimeric G proteins. Recent structural and biophysical studies have highlighted the dynamic nature of GPCRs and G proteins and have identified specific conformational changes important for receptor-mediated nucleotide exchange on Gα. While domain separation within Gα is necessary for GDP release, opening the inter-domain interface is insufficient to stimulate nucleotide exchange. Rather, an activated receptor promotes GDP release by allosterically disrupting the nucleotide-binding site via interactions with the Gα N-termini and C-termini. Highlighting the allosteric nature of GPCRs, recent studies suggest that agonist binding alone poorly stabilizes an active conformation of several receptors. Rather, full stabilization of the receptor in an active state requires formation of the agonist-receptor-G protein ternary complex. In turn, nucleotide-free Gα is able to stabilize conformational changes around the receptor's agonist-binding site to enhance agonist affinity.
(Copyright © 2016 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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