Diverse activation pathways in class A GPCRs converge near the G-protein-coupling region.
Diverse activation pathways in class A GPCRs converge near the G-protein-coupling region.
复制标题
DOI：
10.1038/nature19107
复制
发表时间：
2016-08-25
期刊：
影响因子：
64.8
通讯作者：
Babu, M. Madan
中科院分区：
文献类型：
--
作者：
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
A类G蛋白偶联受体（GPCR）是介导多种生理功能（例如视觉、神经传递和免疫应答）的膜蛋白的大家族。毫不奇怪，它们是近三分之一的处方药物（例如β受体阻滞剂，抗精神病药）的目标。细胞外配体促进GPCR活化，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充当将配体结合口袋连接到受体内的G蛋白偶联区的“激活途径”。不同A类GPCR之间的这些激活途径有多相似？在这里，我们分析了27个GPCR从不同的亚组的结构的活动和/或非活动状态。我们发现，尽管受体之间的激活途径的多样性，途径收敛附近的G蛋白偶联区。这种收敛是介导的一个惊人的保守结构重排的跨膜螺旋3，6和7，释放G蛋白接触残基之间的接触。激活途径的会聚可以解释由不同配体引发的激活步骤如何赋予GPCR结合G蛋白的共同库的能力。
Class A G protein coupled receptors (GPCRs) are a large family of membrane proteins that mediate a wide variety of physiological functions (e.g. vision, neurotransmission, and immune response). Not surprisingly, they are the targets of nearly one-third of all prescribed medicinal drugs (e.g. beta blockers, 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. How similar are these activation pathways across different class A GPCRs? Here, we analysed 27 GPCRs from diverse subgroups for which structures of active and/or inactive states are available. 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 strikingly 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 confer GPCRs the ability to bind a common repertoire of G proteins.
登录
查看更多内容
影响因子：
64.5
作者：
Manglik A;Kim TH;Masureel M;Altenbach C;Yang Z;Hilger D;Lerch MT;Kobilka TS;Thian FS;Hubbell WL;Prosser RS;Kobilka BK
通讯作者：
Kobilka BK
影响因子：
3.7
作者：
Sun D;Ostermaier MK;Heydenreich FM;Mayer D;Jaussi R;Standfuss J;Veprintsev DB
通讯作者：
Veprintsev DB
影响因子：
64.8
作者：
Choe, Hui-Woog;Kim, Yong Ju;Ernst, Oliver P.
通讯作者：
Ernst, Oliver P.
DOI：
10.1073/pnas.1110499108
发表时间：
2011-11-15
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：
Huang W;Manglik A;Venkatakrishnan AJ;Laeremans T;Feinberg EN;Sanborn AL;Kato HE;Livingston KE;Thorsen TS;Kling RC;Granier S;Gmeiner P;Husbands SM;Traynor JR;Weis WI;Steyaert J;Dror RO;Kobilka BK
通讯作者：
Kobilka BK