气候变化领域集成服务门户(CCPortal): Molecular mechanism of biased signaling in a prototypical G protein-coupled receptor

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DOI	10.1126/science.aaz0326
	Molecular mechanism of biased signaling in a prototypical G protein-coupled receptor
	Suomivuori C.-M.; Latorraca N.R.; Wingler L.M.; Eismann S.; King M.C.; Kleinhenz A.L.W.; Skiba M.A.; Staus D.P.; Kruse A.C.; Lefkowitz R.J.; Dror R.O.
发表日期	2020
ISSN	0036-8075
起始页码	881
结束页码	887
卷号	367 期号:6480
英文摘要	Biased signaling, in which different ligands that bind to the same G protein-coupled receptor preferentially trigger distinct signaling pathways, holds great promise for the design of safer and more effective drugs. Its structural mechanism remains unclear, however, hampering efforts to design drugs with desired signaling profiles. Here, we use extensive atomic-level molecular dynamics simulations to determine how arrestin bias and G protein bias arise at the angiotensin II type 1 receptor. The receptor adopts two major signaling conformations, one of which couples almost exclusively to arrestin, whereas the other also couples effectively to a G protein. A long-range allosteric network allows ligands in the extracellular binding pocket to favor either of the two intracellular conformations. Guided by this computationally determined mechanism, we designed ligands with desired signaling profiles. © 2020 American Association for the Advancement of Science. All rights reserved.
关键词	angiotensin 1 receptor beta arrestin 1 beta arrestin 2 G protein coupled receptor rhodopsin chemical binding design method ligand molecular analysis protein signaling allosterism Article carboxy terminal sequence conformational transition controlled study crystal structure human ligand binding molecular dynamics priority journal protein conformation signal transduction structural model
语种	英语
来源机构	Science
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/133694
推荐引用方式 GB/T 7714	Suomivuori C.-M.,Latorraca N.R.,Wingler L.M.,et al. Molecular mechanism of biased signaling in a prototypical G protein-coupled receptor[J]. Science,2020,367(6480).
APA	Suomivuori C.-M..,Latorraca N.R..,Wingler L.M..,Eismann S..,King M.C..,...&Dror R.O..(2020).Molecular mechanism of biased signaling in a prototypical G protein-coupled receptor.,367(6480).
MLA	Suomivuori C.-M.,et al."Molecular mechanism of biased signaling in a prototypical G protein-coupled receptor".367.6480(2020).