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Diverse activation pathways in class A GPCRs converge near the G-protein-coupling region

机译：A类GPCR中的多种激活途径在G蛋白偶联区域附近收敛

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摘要

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(1-4). They are the targets of nearly one-third of all prescribed medicinal drugs(5) such as beta blockers and antipsychotics. GPCR activation is facilitated by extracellular ligands and leads to the recruitment of intracellular G proteins(3,6). 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.
机译：A类G蛋白偶联受体（GPCR）是一大类膜蛋白家族，可介导多种生理功能，包括视觉，神经传递和免疫反应（1-4）。它们是β受体阻滞剂和抗精神病药等所有处方药（5）中近三分之一的目标。细胞外配体促进GPCR的活化，并导致细胞内G蛋白的募集（3,6）。跨膜结构域中残基接触的结构重排用作“激活途径”，将配体结合袋与受体内的G蛋白偶联区相连。为了研究跨A类GPCR的激活途径的相似性，我们分析了来自不同亚组的27种GPCR，这些亚组具有活跃，不活跃或两种状态的结构。在这里，我们显示，尽管受体之间的激活途径不同，但这些途径在G蛋白偶联区域附近会聚。这种收敛是由跨膜螺旋3、6和7之间高度保守的残基接触结构重排介导的，该结构膜释放出与G蛋白接触的残基。激活途径的收敛可以解释由各种配体引发的激活步骤如何使GPCR结合G蛋白的共同库。

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  • 来源
    《Nature》 |2016年第7617期|484-487|共4页
  • 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;

  • 作者单位

    MRC Lab Mol Biol, Francis Crick Ave, Cambridge CB2 0QH, England|Stanford Univ, Sch Med, Dept Mol & Cellular Physiol, 279 Campus Dr, Stanford, CA 94305 USA|Stanford Univ, Dept Comp Sci, 318 Campus Dr, Stanford, CA 94305 USA|Stanford Univ, Inst Computat & Math Engn, 475 Via Ortega, Stanford, CA 94305 USA;

    Paul Scherrer Inst, CH-5232 Villigen, Switzerland;

    CNRS, UMR 5203, Inst Genom Fonct, 141 Rue Cardonille, F-34094 Montpellier 05, France|INSERM, U1191, F-34094 Montpellier, France|Univ Montpellier, F-34094 Montpellier, France;

    Paul Scherrer Inst, CH-5232 Villigen, Switzerland|ETH, Dept Biol, Wolfgang Pauli Str 27, CH-8093 Zurich, Switzerland|Univ Montreal, Dept Biochem, Montreal, PQ H3C 3J7, Canada|Univ Montreal, Inst Res Immunol & Canc, Montreal, PQ H3C 3J7, Canada;

    MRC Lab Mol Biol, Francis Crick Ave, Cambridge CB2 0QH, England;

    Paul Scherrer Inst, CH-5232 Villigen, Switzerland|ETH, Dept Biol, Wolfgang Pauli Str 27, CH-8093 Zurich, Switzerland;

    MRC Lab Mol Biol, Francis Crick Ave, Cambridge CB2 0QH, England;

    Univ Montreal, Dept Biochem, Montreal, PQ H3C 3J7, Canada|Univ Montreal, Inst Res Immunol & Canc, Montreal, PQ H3C 3J7, Canada;

    Paul Scherrer Inst, CH-5232 Villigen, Switzerland|ETH, Dept Biol, Wolfgang Pauli Str 27, CH-8093 Zurich, Switzerland;

    MRC Lab Mol Biol, Francis Crick Ave, Cambridge CB2 0QH, England;

    Paul Scherrer Inst, CH-5232 Villigen, Switzerland|ETH, Dept Biol, Wolfgang Pauli Str 27, CH-8093 Zurich, Switzerland;

    MRC Lab Mol Biol, Francis Crick Ave, Cambridge CB2 0QH, England;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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