Ligand-dependent perturbation of the conformational ensemble for the GPCR β2 adrenergic receptor revealed by HDX.
Ligand-dependent perturbation of the conformational ensemble for the GPCR β2 adrenergic receptor revealed by HDX.
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DOI：
10.1016/j.str.2011.08.001
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发表时间：
2011-10-12
期刊：
影响因子：
5.7
通讯作者：
Griffin, Patrick R.
中科院分区：
文献类型：
--
作者：
West, Graham M.;Chien, Ellen Y. T.;Katritch, Vsevolod;Gatchalian, Jovylyn;Chalmers, Michael J.;Stevens, Raymond C.;Griffin, Patrick R.
G蛋白偶联受体（GPCR）的激活机制及其功能不同的配体的调节仍然是难以捉摸的。采用酰胺氢/氘交换质谱技术，研究了配体诱导的β 2肾上腺素能受体（β2AR）构象变化及其稳定性。差异HDX揭示了配体特异性的受体的构象合奏的能量景观的改变。反向激动剂噻吗洛尔和卡拉唑洛尔被认为是最稳定的，甚至与拮抗剂阿普洛尔相比，特别是在细胞内区域，其中G-蛋白被提议结合，而激动剂异丙肾上腺素诱导最大程度的构象流动性。部分激动剂克仑特罗在反向激动剂和激动剂中均存在。这项研究证实了该受体的区域可塑性，支持GPCR信号传导的当前模型，并表征了仅由功能选择性配体稳定的整个受体序列的独特构象，所有这些都不同于受体的载脂蛋白状态。
Mechanism of G-protein coupled receptor (GPCR) activation and their modulation by functionally distinct ligands remains elusive. Using the technique of amide hydrogen/deuterium exchange coupled with mass spectrometry we examined the ligand-induced changes in conformational states and stability within the beta-2-adrenergic receptor (β2AR). Differential HDX reveals ligand-specific alterations in the energy landscape of the receptor’s conformational ensemble. The inverse agonists timolol and carazolol were found to be most stabilizing even compared to the antagonist alprenolol, notably in intracellular regions where G-proteins are proposed to bind, while the agonist isoproterenol induced the largest degree of conformational mobility. The partial agonist clenbuterol displayed found in both the inverse agonists and the agonist. This study confirms the regional plasticity of the receptor, supports current models for GPCR signaling, and characterizes unique conformations spanning the entire receptor sequence stabilized solely by functionally selective ligands all of which differ from the apo state of the receptor.
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DOI：
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发表时间：
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影响因子：
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作者：
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