Functionally different agonists induce distinct conformations in the G protein coupling domain of the β2 adrenergic receptor
Functionally different agonists induce distinct conformations in the G protein coupling domain of the β2 adrenergic receptor
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DOI：
10.1074/jbc.c100162200
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发表时间：
2001-07-06
影响因子：
4.8
通讯作者：
Kobilka, BK
中科院分区：
文献类型：
--
作者：
Ghanouni, P;Gryczynski, Z;Kobilka, BK
G蛋白偶联受体代表了最大类的药物发现靶点，激活G蛋白偶联受体的药物被分类为激动剂或部分激动剂。为了研究这些不同类型的激活配体调节受体功能的机制，我们直接监测了β 1肾上腺素能受体的G蛋白偶联结构域中配体诱导的构象变化。共价连接到这个域的报告荧光团的荧光寿命分析表明，在没有配体的情况下，这个域围绕一个单一的可检测的构象振荡。与拮抗剂结合不会改变这种构象，但会降低结构域的柔性。然而，当β 1肾上腺素能受体与完全激动剂结合时，G蛋白偶联结构域以两种不同的构象存在。此外，完全激动剂诱导的构象可以与部分激动剂诱导的构象区分开。这些结果为拮抗剂结合的结构后果以及激动和部分激动的基础提供了新的见解。
G protein-coupled receptors represent the largest class of drug discovery targets, Drugs that activate G protein-coupled receptors are classified as either agonists or partial agonists, To study the mechanism whereby these different classes of activating ligands modulate receptor function, we directly monitored ligand-induced conformational changes in the G protein-coupling domain of the P, adrenergic receptor. Fluorescence lifetime analysis of a reporter fluorophore covalently attached to this domain revealed that, in the absence of ligands, this domain oscillates around a single detectable conformation. Binding to an antagonist does not change this conformation but does reduce the flexibility of the domain. However, when the P, adrenergic receptor is bound to a full agonist, the G protein coupling domain exists in two distinct conformations. Moreover, the conformations induced by a full agonist can be distinguished from those induced by partial agonists. These results provide new insight into the structural consequence of antagonist binding and the basis of agonism and partial agonism.