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Molecular control of δ-opioid receptor signalling

机译：δ阿片受体信号传导的分子控制

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摘要

Opioids represent widely prescribed and abused medications, although their signal transduction mechanisms are not well understood. Here we present the 1.8 A high-resolution crystal structure of the human 8-opioid receptor (δ-OR), revealing the presence and fundamental role of a sodium ion in mediating allosteric control of receptor functional selectivity and constitutive activity. The distinctive δ-OR sodium ion site architecture is centrally located in a polar interaction network in the seven-transmembrane bundle core, with the sodium ion stabilizing a reduced agonist affinity state, and thereby modulating signal transduction. Site-directed mutagenesis and functional studies reveal that changing the allosteric sodium site residue Asn 131 to an alanine or a valine augments constitutive β- arrestin-mediated signalling. Asp95Ala, Asn310Ala and Asn314Ala mutations transform classical δ-opioid antagonists such as naltrindole into potent β-arrestin-biased agonists. The data establish the molecular basis for allosteric sodium ion control in opioid signalling, revealing that sodium-coordinating residues act as 'efficacy switches' at a prototypic G-protein-coupled receptor.%阿片类药物受体在包括"痛觉缺失"、意识、运动控制和情绪在内的很多生理过程中介导内源性和外源性阿片类药物的作用。这篇论文以1.8Å的分辨率报告了人δ-阿片受体的X-射线晶体结构，它显示存在似乎介导这一"G-蛋白耦合受体"的变构控制的一个钠离子。定点诱变和功能研究表明，将该"变构钠点"(allosteric sodium site)中的关键氨基酸诱变成为丙氨酸，会将拮抗药物"纳曲吲哚"变成一种强效的β-arrestin-biased促效药物。另外也比较明显的是一个"变构钠结合袋"，它可能有助于亚型选择性δ-阿片受体促效药物和拮抗药物的研发一一正构配体向这个"袋"内的延伸可能会生成具有更有利药理特性的"bitopic"正构/变构化合物。
机译：阿片类药物代表了广泛开出的处方药和滥用药物，尽管它们的信号转导机制尚未得到很好的了解。在这里，我们介绍了人类8类阿片受体（δ-OR）的1.8 A高分辨率晶体结构，揭示了钠离子在介导变构控制受体功能选择性和组成活性中的存在及其基本作用。独特的δ-OR钠离子位点结构位于七跨膜束核心中的极性相互作用网络的中心，钠离子可稳定降低的激动剂亲和力状态，从而调节信号转导。定点诱变和功能研究表明，将变构钠位点残基Asn 131更改为丙氨酸或缬氨酸可增强β-抑制蛋白介导的组成型信号传导。 Asp95Ala，Asn310Ala和Asn314Ala突变可将经典的δ阿片类拮抗剂（如纳丁酮）转化为有效的β-arrestin偏置的激动剂。数据建立了阿片样物质信号传导中变构钠离子控制的分子基础，揭示了钠协同残基在原型G蛋白偶联受体上起着“功效转换”的作用。％阿片类药物受体在包括“痛觉缺失”，意识，运动控制和情绪内部的很多生理过程中介导内源性和外源性阿片类药物的作用。本文以1.8Å的分辨率报告了人δ-阿片受体的X-射线晶体结构，它显示存在似乎介导的这一“ G-蛋白替代受体”的变构控制的一个钠离子。定点诱变和功能研究表明，称为“变构钠点”（变构钠部位）中的关键氨基酸捕获变成为丙氨酸，可以掺入抗药物“纳曲替丁”变成一种强效的β-arrestin-biased的促效药物。另外也比较明显的是一个“变构钠结合袋”，它可能有助于亚型选择性δ-阿片受体促效药物和替代抗药物的研发一一正构配体向这个“袋”的内部延伸可能会生成具有更有利药理特性的“ bitopic”正构/变构化合物。

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  • 来源
    《Nature》 |2014年第7487期|191-196121|共7页
  • 作者

    Gustavo Fenalti; Patrick M. Giguere; Vsevolod Katritch; Xi-Ping Huang; Aaron A. Thompson; Vadim Cherezov; Bryan L. Roth; Raymond C. Stevens;

  • 作者单位

    Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA;

    National Institute of Mental Health Psychoactive Drug Screening Program and Department of Pharmacology and Division of Chemical Biology and Medicinai Chemistry, University of North Carolina Chapel Hill Medical School, Chapel Hill, North Carolina 27599, USA;

    Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA;

    National Institute of Mental Health Psychoactive Drug Screening Program and Department of Pharmacology and Division of Chemical Biology and Medicinai Chemistry, University of North Carolina Chapel Hill Medical School, Chapel Hill, North Carolina 27599, USA;

    Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA;

    Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA;

    National Institute of Mental Health Psychoactive Drug Screening Program and Department of Pharmacology and Division of Chemical Biology and Medicinai Chemistry, University of North Carolina Chapel Hill Medical School, Chapel Hill, North Carolina 27599, USA;

    Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, 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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