Venkatakrishnan A J, Deupi Xavier, Lebon Guillaume, Heydenreich Franziska M, Flock Tilman, Miljus Tamara, Balaji Santhanam, Bouvier Michel, Veprintsev Dmitry B, Tate Christopher G, Schertler Gebhard F X, Babu M Madan
Nature. 2016 Aug 25;536(7617):484-7. doi: 10.1038/nature19107. Epub 2016 Aug 15.
Class A G-protein-coupled receptors (GPCRs) are a large family of membrane proteins that mediate a wide variety of physiological functions, including vision, neurotransmission and immune responses. They are the targets of nearly one-third of all prescribed medicinal drugs such as beta blockers and antipsychotics. GPCR activation is facilitated by extracellular ligands and leads to the recruitment of intracellular G proteins. Structural rearrangements of residue contacts in the transmembrane domain serve as 'activation pathways' that connect the ligand-binding pocket to the G-protein-coupling region within the receptor. In order to investigate the similarities in activation pathways across class A GPCRs, we analysed 27 GPCRs from diverse subgroups for which structures of active, inactive or both states were available. Here we show that, despite the diversity in activation pathways between receptors, the pathways converge near the G-protein-coupling region. This convergence is mediated by a highly conserved structural rearrangement of residue contacts between transmembrane helices 3, 6 and 7 that releases G-protein-contacting residues. The convergence of activation pathways may explain how the activation steps initiated by diverse ligands enable GPCRs to bind a common repertoire of G proteins.
A类G蛋白偶联受体（GPCRs）是一大类膜蛋白，介导多种生理功能，包括视觉、神经传递和免疫反应。它们是近三分之一的处方药（如β受体阻滞剂和抗精神病药物）的作用靶点。细胞外配体促进GPCR的激活，并导致细胞内G蛋白的募集。跨膜结构域中残基接触的结构重排作为“激活途径”，将配体结合口袋与受体内的G蛋白偶联区域连接起来。为了研究A类GPCRs激活途径的相似性，我们分析了来自不同亚组的27种GPCRs，这些GPCRs的活性、非活性或两种状态的结构均可用。我们在此表明，尽管受体之间的激活途径存在差异，但这些途径在G蛋白偶联区域附近汇聚。这种汇聚是由跨膜螺旋3、6和7之间残基接触的高度保守结构重排介导的，该重排释放了与G蛋白接触的残基。激活途径的汇聚可能解释了由不同配体启动的激活步骤如何使GPCRs结合共同的G蛋白库。
