Structural Insights into the Dynamic Process of β2-Adrenergic Receptor Signaling.
Structural Insights into the Dynamic Process of β2-Adrenergic Receptor Signaling.
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DOI：
10.1016/j.cell.2015.04.043
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发表时间：
2015-05-21
期刊：
影响因子：
64.5
通讯作者：
Kobilka BK
中科院分区：
文献类型：
--
作者：
Manglik A;Kim TH;Masureel M;Altenbach C;Yang Z;Hilger D;Lerch MT;Kobilka TS;Thian FS;Hubbell WL;Prosser RS;Kobilka BK
G蛋白偶联受体（GPCR）将信号从细胞外环境传递到细胞内蛋白质。为了获得信号传导过程中细胞外配体对受体胞质构象调节的结构洞察，我们使用19 F-氟NMR和双电子-电子共振光谱检查了β2-肾上腺素能受体（β2AR）胞质结构域的结构动力学。这些研究表明，未配体和反向激动剂结合的β2AR主要存在于两种在数百微秒内交换的非活性构象中。尽管激动剂将平衡向能够接合细胞质G蛋白的构象移动，但它们这样做是不完全的，导致构象异质性增加以及非活性、中间和活性状态的共存。完全转变为活性构象需要随后与G蛋白或细胞内G蛋白模拟物相互作用。这些研究表明，激动剂结合位点和G蛋白偶联界面的松散变构偶联通常可能是许多GPCR观察到的复杂信号传导行为的原因。
G protein-coupled receptors (GPCRs) transduce signals from the extracellular environment to intracellular proteins. To gain structural insight into the regulation of receptor cytoplasmic conformations by extracellular ligands during signaling, we examine the structural dynamics of the cytoplasmic domain of the β2-adrenergic receptor (β2AR) using 19F-fluorine NMR and double electron-electron resonance spectroscopy. These studies show that unliganded and inverse-agonist-bound β2AR exists predominantly in two inactive conformations that exchange within hundreds of microseconds. Although agonists shift the equilibrium towards a conformation capable of engaging cytoplasmic G proteins, they do so incompletely, resulting in increased conformational heterogeneity and the coexistence of inactive, intermediate and active states. Complete transition to the active conformation requires subsequent interaction with a G-protein or an intracellular G protein mimetic. These studies demonstrate a loose allosteric coupling of the agonist-binding site and G protein-coupling interface that may generally be responsible for the complex signaling behavior observed for many GPCRs.
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影响因子：
16.6
作者：
通讯作者：
--
影响因子：
1
作者：
Hagelueken, Gregor;Ward, Richard;Naismith, James H.;Schiemann, Olav
通讯作者：
Schiemann, Olav
DOI：
10.1073/pnas.0811065106
发表时间：
2009-03-24
影响因子：
11.1
作者：
Dror, Ron O.;Arlow, Daniel H.;Shaw, David E.
通讯作者：
Shaw, David E.
影响因子：
64.8
作者：
Choe, Hui-Woog;Kim, Yong Ju;Ernst, Oliver P.
通讯作者：
Ernst, Oliver P.
DOI：
10.1073/pnas.1110499108
发表时间：
2011-11-15
影响因子：
11.1
作者：
Dror, Ron O.;Arlow, Daniel H.;Shaw, David E.
通讯作者：
Shaw, David E.