Multiple ligand-specific conformations of the β2-adrenergic receptor.
Multiple ligand-specific conformations of the β2-adrenergic receptor.
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DOI：
10.1038/nchembio.634
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发表时间：
2011-08-21
影响因子：
14.8
通讯作者：
Lefkowitz, Robert J.
中科院分区：
文献类型：
--
作者：
Kahsai, Alem W.;Xiao, Kunhong;Rajagopal, Sudarshan;Ahn, Seungkirl;Shukla, Arun K.;Sun, Jinpeng;Oas, Terrence G.;Lefkowitz, Robert J.
七次跨膜受体 (7TMR)，也称为 G 蛋白偶联受体 (GPCR)，代表最大一类药物靶点，它们可以通过几种不同的机制发出信号，包括由 G 蛋白和多功能接头蛋白 β-抑制蛋白介导的机制。此外，已经鉴定出几种对这些不同信号传导途径具有不同功效的受体配体。然而，这种“偏向激动”背后的结构基础和机制仍然很大程度上未知。在这里，我们开发了一种定量质谱策略，可测量各个侧链的特定反应性，以研究由九种功能不同的配体占据的β2-肾上腺素受体的动态构象变化。出乎意料的是，只有少数残基显示出与经典激动作用一致的反应模式，而大多数残基即使在功能相似的配体之间也显示出不同的反应模式。这些发现表明，与受体活性的两种状态模型相反，不同配体诱导的受体构象存在显着的变异性，这对新治疗剂的设计具有重要意义。
Seven-transmembrane receptors (7TMRs), also called G protein–coupled receptors (GPCRs), represent the largest class of drug targets, and they can signal through several distinct mechanisms including those mediated by G proteins and the multifunctional adaptor proteins β-arrestins. Moreover, several receptor ligands with differential efficacies toward these distinct signaling pathways have been identified. However, the structural basis and mechanism underlying this ‘biased agonism’ remains largely unknown. Here, we develop a quantitative mass spectrometry strategy that measures specific reactivities of individual side chains to investigate dynamic conformational changes in the β2-adrenergic receptor occupied by nine functionally distinct ligands. Unexpectedly, only a minority of residues showed reactivity patterns consistent with classical agonism, whereas the majority showed distinct patterns of reactivity even between functionally similar ligands. These findings demonstrate, contrary to two-state models for receptor activity, that there is significant variability in receptor conformations induced by different ligands, which has significant implications for the design of new therapeutic agents.
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影响因子：
4.8
作者：
Ghanouni, P;Gryczynski, Z;Kobilka, BK
通讯作者：
Kobilka, BK
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：
通讯作者：
--
DOI：
10.1073/pnas.0710487105
发表时间：
2008-01-08
影响因子：
11.1
作者：
Barnea, Gilad;Strapps, Walter;Lee, Kevin J.
通讯作者：
Lee, Kevin J.
影响因子：
6.3
作者：
Lefkowitz, R. J.
通讯作者：
Lefkowitz, R. J.