Delineating the conformational landscape of the adenosine A2A receptor during G protein coupling

被引：88

作者：

Huang, Shuya Kate ^{[1
]}

Pandey, Aditya ^{[1
,2
]}

Duy Phuoc Tran ^{[3
]}

Villanueva, Nicolas L. ^{[4
]}

Kitao, Akio ^{[3
]}

Sunahara, Roger K. ^{[4
]}

Sljoka, Adnan ^{[1
,5
]}

Prosser, R. Scott ^{[1
,2
]}

机构：

[1] Univ Toronto, Dept Chem, UTM, 3359 Rd North, Mississauga, ON L5L 1C6, Canada

[2] Univ Toronto, Dept Biochem, 1 Kings Coll Circle, Toronto, ON M5S 1A8, Canada

[3] Tokyo Inst Technol, Sch Life Sci & Technol, Meguro Ku, 2-12-1 Ookayama, Tokyo 2121, Japan

[4] Univ Calif San Diego, Dept Pharmacol, Sch Med, 9500 Gilman Dr, La Jolla, CA 92093 USA

[5] RIKEN, RIKEN Ctr Adv Intelligence Project, Chuo Ku, 1-4-1 Nihombashi, Tokyo 1030027, Japan

来源：

CELL | 2021年 / 184卷 / 07期

基金：

加拿大健康研究院; 日本科学技术振兴机构; 加拿大自然科学与工程研究理事会;

关键词：

BETA(2)-ADRENERGIC RECEPTOR; ALLOSTERIC REGULATION; LIGAND EFFICACY; DYNAMIC PROCESS; IONIC LOCK; ACTIVATION; INSIGHTS; FLEXIBILITY; EQUILIBRIA; RESOLUTION;

D O I：

10.1016/j.cell.2021.02.041

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

G-protein-coupled receptors (GPCRs) represent a ubiquitous membrane protein family and are important drug targets. Their diverse signaling pathways are driven by complex pharmacology arising from a conformational ensemble rarely captured by structural methods. Here, fluorine nuclear magnetic resonance spectroscopy (F-19 NMR) is used to delineate key functional states of the adenosine A(2A) receptor (A(2A)R) complexed with heterotrimeric G protein (G alpha(s)beta(1)gamma(2)) in a phospholipid membrane milieu. Analysis of A(2A)R spectra as a function of ligand, G protein, and nucleotide identifies an ensemble represented by inactive states, a G-protein-bound activation intermediate, and distinct nucleotide-free states associated with either partial- or fullagonist-driven activation. The G beta gamma subunit is found to be critical in facilitating ligand-dependent allosteric transmission, as shown by F-19 NMR, biochemical, and computational studies. The results provide a mechanistic basis for understanding basal signaling, efficacy, precoupling, and allostery in GPCRs.

引用

页码：1884 / +

页数：25

共 71 条

[1] Activation of the β2-adrenergic receptor involves disruption of an ionic lock between the cytoplasmic ends of transmembrane segments 3 and 6 [J].