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Allosteric coupling from G protein to the agonist-binding pocket in GPCRs

机译：G蛋白中G蛋白与激动剂结合口袋的变构偶联

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摘要

G-protein-coupled receptors (GPCRs) remain the primary conduit by which cells detect environmental stimuli and communicate with each other(1). Upon activation by extracellular agonists, these seven-transmembrane-domain-containing receptors interact with heterotrimeric G proteins to regulate downstream second messenger and/or protein kinase cascades(1). Crystallographic evidence from a prototypic GPCR, the beta(2)-adrenergic receptor (beta(2)AR), in complex with its cognate G protein, Gs, has provided a model for how agonist binding promotes conformational changes that propagate through the GPCR and into the nucleotide-binding pocket of the G protein a-subunit to catalyse GDP release, the key step required for GTP binding and activation of G proteins(2). The structure also offers hints about how G-protein binding may, in turn, allosterically influence ligand binding. Here we provide functional evidence that G-protein coupling to the beta(2)AR stabilizes a 'closed' receptor conformation characterized by restricted access to and egress from the hormone-binding site. Surprisingly, the effects of G protein on the hormone-binding site can be observed in the absence of a bound agonist, where G-protein coupling driven by basal receptor activity impedes the association of agonists, partial agonists, antagonists and inverse agonists. The ability of bound ligands to dissociate from the receptor is also hindered, providing a structural explanation for the G-protein-mediated enhancement of agonist affinity, which has been observed for many GPCR-G-protein pairs. Our data also indicate that, in contrast to agonist binding alone, coupling of a G protein in the absence of an agonist stabilizes large structural changes in a GPCR. The effects of nucleotide-free G protein on ligand-binding kinetics are shared by other members of the superfamily of GPCRs, suggesting that a common mechanism may underlie G-protein-mediated enhancement of agonist affinity.
机译：G蛋白偶联受体（GPCR）仍然是细胞检测环境刺激并相互交流的主要管道（1）。在细胞外激动剂激活后，这些包含七个跨膜结构域的受体与异三聚体G蛋白相互作用，以调节下游的第二信使和/或蛋白激酶级联反应（1）。原型GPCR的结晶学证据表明，β（2）-肾上腺素能受体（beta（2）AR）及其同源G蛋白Gs结合在一起，为激动剂结合如何促进构象变化（通过GPCR和进入G蛋白a亚基的核苷酸结合口袋以催化GDP释放，这是GTP结合和G蛋白活化所需的关键步骤（2）。该结构还提供了有关G蛋白结合可能反过来如何变构影响配体结合的暗示。在这里，我们提供功能性证据，证明与β（2）AR偶联的G蛋白稳定了“封闭”受体构象，该构象的特征是进入和离开激素结合位点受限。令人惊讶地，在不存在结合激动剂的情况下可以观察到G蛋白对激素结合位点的作用，其中由基础受体活性驱动的G蛋白偶联阻碍了激动剂，部分激动剂，拮抗剂和反向激动剂的缔合。结合的配体从受体解离的能力也受到阻碍，这为G蛋白介导的激动剂亲和力增强提供了结构性解释，这已在许多GPCR-G蛋白对中观察到。我们的数据还表明，与单独的激动剂结合相反，在不存在激动剂的情况下偶联G蛋白可以稳定GPCR中的大结构变化。 GPCR超家族的其他成员也共享无核苷酸的G蛋白对配体结合动力学的影响，这表明共同的机制可能是G蛋白介导的激动剂亲和力增强的基础。

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  • 来源
    《Nature》 |2016年第7610期|182-186|共5页
  • 作者

    DeVree Brian T.; Mahoney Jacob P.; Velez-Ruiz Gisselle A.; Rasmussen Soren G. F.; Kuszak Adam J.; Edwald Elin; Fung Juan-Jose; Manglik Aashish; Masureel Matthieu; Du Yang; Matt Rachel A.; Pardon Els; Steyaert Jan; Kobilka Brian K.; Sunahara Roger K.;

  • 作者单位

    Univ Michigan, Sch Med, Dept Pharmacol, Ann Arbor, MI 48109 USA;

    Univ Michigan, Sch Med, Dept Pharmacol, Ann Arbor, MI 48109 USA;

    Univ Michigan, Sch Med, Dept Pharmacol, Ann Arbor, MI 48109 USA;

    Stanford Univ, Dept Cellular & Mol Physiol, Palo Alto, CA 94305 USA;

    Univ Michigan, Sch Med, Dept Pharmacol, Ann Arbor, MI 48109 USA;

    Univ Michigan, Sch Med, Dept Pharmacol, Ann Arbor, MI 48109 USA;

    Stanford Univ, Dept Cellular & Mol Physiol, Palo Alto, CA 94305 USA;

    Stanford Univ, Dept Cellular & Mol Physiol, Palo Alto, CA 94305 USA;

    Stanford Univ, Dept Cellular & Mol Physiol, Palo Alto, CA 94305 USA;

    Stanford Univ, Dept Cellular & Mol Physiol, Palo Alto, CA 94305 USA;

    Stanford Univ, Dept Cellular & Mol Physiol, Palo Alto, CA 94305 USA;

    VUB, Struct Biol Res Ctr, VIB, Pl Laan 2, B-1050 Brussels, Belgium;

    VUB, Struct Biol Brussels, Pl Laan 2, B-1050 Brussels, Belgium;

    Stanford Univ, Dept Cellular & Mol Physiol, Palo Alto, CA 94305 USA;

    Univ Michigan, Sch Med, Dept Pharmacol, Ann Arbor, MI 48109 USA|Univ Calif San Diego, Dept Pharmacol, Sch Med, 9500 Gilman Dr, La Jolla, CA 92093 USA;

  • 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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