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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Ligands and signaling proteins govern the conformational landscape explored by a G protein-coupled receptor
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Ligands and signaling proteins govern the conformational landscape explored by a G protein-coupled receptor

机译：配体和信号蛋白控制G蛋白偶联受体探索的构象态势

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摘要

The dynamic character of G protein-coupled receptors is essential to their function. However, the details of how ligands stabilize a particular conformation to selectively activate a signaling pathway and how signaling proteins affect this conformational repertoire remain unclear. Using a prototypical peptide-activated class A G protein-coupled receptor (GPCR), the ghrelin receptor, reconstituted as a monomer into lipid discs and labeled with a fluorescent conformational reporter, we demonstrate that ligand efficacy and functional selectivity are directly related to different receptor conformations. Of importance, our data bring direct evidence that distinct effector proteins affect the conformational landscape of the ghrelin receptor in different ways. Whereas G proteins affect the balance between active and inactive receptor substates in favor of the active state, agonist-induced arrestin recruitment is accompanied by a marked change in the structural features of the receptor that adopt a conformation different from that observed in the absence of arrestin. In contrast to G proteins and arrestins, ji-AP2 has no significant effect on the organization of the transmembrane core of the receptor. Such a modulation of a GPCR conformational landscape by pharmacologically distinct ligands and effectors provides insights into the structural bases that decisively affect ligand efficacy and subsequent biological responses. This is also likely to have major implications for the design of drugs activating specific GPCR-associated signaling pathways.
机译：G蛋白偶联受体的动态特性对其功能至关重要。然而，关于配体如何稳定特定构象以选择性激活信号传导途径以及信号蛋白如何影响该构象库的细节尚不清楚。使用原型肽激活的AG类蛋白偶联受体（GPCR），ghrelin受体，以单体形式重构到脂质盘中，并用荧光构象报道分子标记，我们证明配体功效和功能选择性与不同的受体构象直接相关。重要的是，我们的数据直接证明了不同的效应蛋白会以不同的方式影响ghrelin受体的构象。 G蛋白影响活性和非活性受体亚状态之间的平衡，有利于活性状态，而激动剂诱导的抑制蛋白募集伴随着受体结构特征的显着变化，其构象与在不存在抑制蛋白的情况下观察到的构象不同。与G蛋白和抑制蛋白相反，ji-AP2对受体的跨膜核心组织没有显着影响。通过药理学上不同的配体和效应子对GPCR构象景观的这种调节，提供了对决定性影响配体功效和后续生物学反应的结构基础的见解。这也可能对激活特异性GPCR相关信号通路的药物设计产生重大影响。

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  • 作者

    Sophie Mary; Marjorie Damian; Maxime Louet; Nicolas Floquet; Jean-Alain Fehrentz; Jacky Marie; Jean Martinez; Jean-Louis Baneres;

  • 作者单位

    Centre National de la Recherche Scientifique, Unite Mixte de Recherche 5247, and Universite Montpellier 1 et 2, Faculte de Pharmacie, Institut des Biomolecules Max Mousseron, 34093 Montpellier Cedex 05, France;

    Centre National de la Recherche Scientifique, Unite Mixte de Recherche 5247, and Universite Montpellier 1 et 2, Faculte de Pharmacie, Institut des Biomolecules Max Mousseron, 34093 Montpellier Cedex 05, France;

    Centre National de la Recherche Scientifique, Unite Mixte de Recherche 5247, and Universite Montpellier 1 et 2, Faculte de Pharmacie, Institut des Biomolecules Max Mousseron, 34093 Montpellier Cedex 05, France;

    Centre National de la Recherche Scientifique, Unite Mixte de Recherche 5247, and Universite Montpellier 1 et 2, Faculte de Pharmacie, Institut des Biomolecules Max Mousseron, 34093 Montpellier Cedex 05, France;

    Centre National de la Recherche Scientifique, Unite Mixte de Recherche 5247, and Universite Montpellier 1 et 2, Faculte de Pharmacie, Institut des Biomolecules Max Mousseron, 34093 Montpellier Cedex 05, France;

    Centre National de la Recherche Scientifique, Unite Mixte de Recherche 5247, and Universite Montpellier 1 et 2, Faculte de Pharmacie, Institut des Biomolecules Max Mousseron, 34093 Montpellier Cedex 05, France;

    Centre National de la Recherche Scientifique, Unite Mixte de Recherche 5247, and Universite Montpellier 1 et 2, Faculte de Pharmacie, Institut des Biomolecules Max Mousseron, 34093 Montpellier Cedex 05, France;

    Centre National de la Recherche Scientifique, Unite Mixte de Recherche 5247, and Universite Montpellier 1 et 2, Faculte de Pharmacie, Institut des Biomolecules Max Mousseron, 34093 Montpellier Cedex 05, France;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    membrane protein; structural repertoire; biased ligands; constitutive activity;

    机译：膜蛋白结构库偏配体本构活动;

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