Activation mechanism of the β2-adrenergic receptor
Activation mechanism of the β2-adrenergic receptor
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DOI：
10.1073/pnas.1110499108
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发表时间：
2011-11-15
影响因子：
11.1
通讯作者：
Shaw, David E.
中科院分区：
文献类型：
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作者：
Dror, Ron O.;Arlow, Daniel H.;Shaw, David E.
三分之一的市售药物通过与G蛋白偶联受体（GPCR）结合并触发或阻止受体激活来发挥作用。尽管最近的晶体结构提供了GPCR的活性和非活性功能状态的快照，但这些结构并没有揭示GPCR在这些状态之间转变的机制。在这里，我们提出了一个激活机制的β（2）-肾上腺素能受体，一个原型GPCR，基于原子水平的模拟，其中激动剂结合受体自发地从活性过渡到非活性晶体学观察到的构象。一个松散耦合的变构网络，包括三个区域，每个区域可以单独切换之间的多种不同的构象，链接在细胞外药物结合位点的小扰动在细胞内G-蛋白结合位点的大构象变化。我们的模拟还表现出一个中间体，可能代表一个受体构象的G蛋白结合在激活过程中，并表明，在受体激活过程中的第一个结构变化往往发生在细胞内的受体，远离药物结合位点。通过捕捉原子细节的基本信号传导过程，我们的研究结果可能为设计药物提供基础，通过稳定特定受体构象更精确地控制受体信号传导。
A third of marketed drugs act by binding to a G-protein-coupled receptor (GPCR) and either triggering or preventing receptor activation. Although recent crystal structures have provided snapshots of both active and inactive functional states of GPCRs, these structures do not reveal the mechanism by which GPCRs transition between these states. Here we propose an activation mechanism for the beta(2)-adrenergic receptor, a prototypical GPCR, based on atomic-level simulations in which an agonist-bound receptor transitions spontaneously from the active to the inactive crystallographically observed conformation. A loosely coupled allosteric network, comprising three regions that can each switch individually between multiple distinct conformations, links small perturbations at the extracellular drug-binding site to large conformational changes at the intracellular G-protein-binding site. Our simulations also exhibit an intermediate that may represent a receptor conformation to which a G protein binds during activation, and suggest that the first structural changes during receptor activation often take place on the intracellular side of the receptor, far from the drug-binding site. By capturing this fundamental signaling process in atomic detail, our results may provide a foundation for the design of drugs that control receptor signaling more precisely by stabilizing specific receptor conformations.