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Angiotensin and biased analogs induce structurally distinct active conformations within a GPCR
Science ( IF 56.9 ) Pub Date : 2020-02-20 , DOI: 10.1126/science.aay9813
Laura M Wingler 1, 2 , Meredith A Skiba 3 , Conor McMahon 3 , Dean P Staus 1, 2 , Alissa L W Kleinhenz 1, 2, 4 , Carl-Mikael Suomivuori 5, 6, 7 , Naomi R Latorraca 5, 6, 7, 8 , Ron O Dror 5, 6, 7, 8 , Robert J Lefkowitz 1, 2, 9 , Andrew C Kruse 3
Affiliation  

Choosing the drug to fit the protein Many approved drugs bind to G protein–coupled receptors (GPCRs). A challenge in targeting GPCRs is that different ligands preferentially activate different signaling pathways. Two papers show how biased signaling arises for the angiotensin II type 1 receptor that couples to two signaling partners (G proteins and arrestins). Suomivuori et al. used large-scale atomistic simulations to show that coupling to the two pathways is through two distinct GPCR conformations and that extracellular ligands favor one or the other conformation. Wingler et al. present crystal structures of the same receptor bound to ligands with different bias profiles. These structures show conformational changes in and around the binding pocket that match those observed in simulations. This work could provide a framework for the rational design of drugs that are more effective and have fewer side effects. Science, this issue p. 881, p. 888 Crystal structures elucidate how ligands select among signaling conformations of a G protein–coupled receptor. Biased agonists of G protein–coupled receptors (GPCRs) preferentially activate a subset of downstream signaling pathways. In this work, we present crystal structures of angiotensin II type 1 receptor (AT1R) (2.7 to 2.9 angstroms) bound to three ligands with divergent bias profiles: the balanced endogenous agonist angiotensin II (AngII) and two strongly β-arrestin–biased analogs. Compared with other ligands, AngII promotes more-substantial rearrangements not only at the bottom of the ligand-binding pocket but also in a key polar network in the receptor core, which forms a sodium-binding site in most GPCRs. Divergences from the family consensus in this region, which appears to act as a biased signaling switch, may predispose the AT1R and certain other GPCRs (such as chemokine receptors) to adopt conformations that are capable of activating β-arrestin but not heterotrimeric Gq protein signaling.

中文翻译:

血管紧张素和偏向类似物在 GPCR 内诱导结构不同的活性构象

选择适合蛋白质的药物 许多批准的药物与 G 蛋白偶联受体 (GPCR) 结合。靶向 GPCR 的一个挑战是不同的配体优先激活不同的信号通路。两篇论文展示了血管紧张素 II 1 型受体如何与两个信号伙伴(G 蛋白和抑制素)偶联的偏向信号发生。索米沃里等人。使用大规模原子模拟来表明通过两种不同的 GPCR 构象与两种途径的耦合,并且细胞外配体有利于一种或另一种构象。温格勒等人。呈现与具有不同偏向特征的配体结合的相同受体的晶体结构。这些结构显示出与模拟中观察到的相匹配的结合口袋内部和周围的构象变化。这项工作可以为合理设计更有效且副作用更少的药物提供一个框架。科学,这个问题 p。881 页。888 晶体结构阐明了配体如何在 G 蛋白偶联受体的信号构象中进行选择。G 蛋白偶联受体 (GPCR) 的偏向激动剂优先激活下游信号通路的一个子集。在这项工作中,我们展示了血管紧张素 II 1 型受体 (AT1R)(2.7 至 2.9 埃)的晶体结构,该受体与具有不同偏向性的三种配体结合:平衡内源性激动剂血管紧张素 II (AngII) 和两种强烈偏向 β-抑制蛋白的类似物. 与其他配体相比,AngII 不仅在配体结合口袋的底部而且在受体核心的关键极性网络中促进了更大量的重排,在大多数 GPCR 中形成钠结合位点。该区域与家族共识的分歧,似乎充当了一个偏向的信号开关,可能使 AT1R 和某些其他 GPCR(如趋化因子受体)倾向于采用能够激活 β-抑制蛋白但不能激活异三聚体 Gq 蛋白信号的构象.
更新日期:2020-02-20
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