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Shared structural mechanisms of general anaesthetics and benzodiazepines

机译：一般麻醉剂和苯并二氮杂卓的共同结构机制

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摘要

Most general anaesthetics and classical benzodiazepine drugs act through positive modulation of gamma-aminobutyric acid type A (GABA(A)) receptors to dampen neuronal activity in the brain(1-5). However, direct structural information on the mechanisms of general anaesthetics at their physiological receptor sites is lacking. Here we present cryo-electron microscopy structures of GABA(A)receptors bound to intravenous anaesthetics, benzodiazepines and inhibitory modulators. These structures were solved in a lipidic environment and are complemented by electrophysiology and molecular dynamics simulations. Structures of GABA(A)receptors in complex with the anaesthetics phenobarbital, etomidate and propofol reveal both distinct and common transmembrane binding sites, which are shared in part by the benzodiazepine drug diazepam. Structures in which GABA(A)receptors are bound by benzodiazepine-site ligands identify an additional membrane binding site for diazepam and suggest an allosteric mechanism for anaesthetic reversal by flumazenil. This study provides a foundation for understanding how pharmacologically diverse and clinically essential drugs act through overlapping and distinct mechanisms to potentiate inhibitory signalling in the brain.Cryo-electron microscopy structures of GABA(A)receptors bound to intravenous anaesthetics and benzodiazepines reveal both common and distinct transmembrane binding sites, and show that the mechanisms of action of anaesthetics partially overlap with those of benzodiazepines.
机译：大多数全身麻醉剂和古典苯二氮卓药通过γ-氨基丁酸类型A的阳性调节（GABA（A））受体在大脑中抑制神经元活性（1-5）。然而，缺乏关于在其生理受体遗址上的全部麻醉机制的直接结构信息。在这里，我们呈现与静脉内麻醉剂，苯并二氮杂卓和抑制剂结合的GABA（A）受体的冷冻电子显微镜结构。这些结构在脂质环境中得到解决，并且通过电生理学和分子动力学模拟辅成。 GABA（A）受体的结构与麻醉剂苯甲苯丙胺，戊胺和异丙酚的综合性揭示了不同且常见的跨膜结合位点，其部分由苯二氮卓药二氮杂泮分组。 GABA（A）受体由苯并二氮杂卓 - 位点配体束缚的结构鉴定了一种额外的二氮杂民动物的膜结合位点，并表明了氟氮醌麻醉逆转的变构机制。本研究为了解药理学上多样化和临床基本原因是如何通过重叠和不同机制来对脑大脑中的抑制信号传导的重叠和不同机制作用的基础。GABA（A）受体与静脉内麻醉剂结合的GABA（A）受体和苯并二氮杂卓的影响揭示了常见和截然不同的跨膜结合位点，并表明麻醉剂的作用机制部分与苯二氮卓卓的重叠。

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  • 来源
    《Nature》 |2020年第7824期|303-308|共6页
  • 作者

    Kim Jeong Joo; Gharpure Anant; Teng Jinfeng; Zhuang Yuxuan; Howard Rebecca J.; Zhu Shaotong; Noviello Colleen M.; Walsh Richard M. Jr.; Lindahl Erik; Hibbs Ryan E.;

  • 作者单位

    Univ Texas Southwestern Med Ctr Dallas Dept Neurosci Dallas TX 75390 USA;

    Univ Texas Southwestern Med Ctr Dallas Dept Neurosci Dallas TX 75390 USA;

    Univ Texas Southwestern Med Ctr Dallas Dept Neurosci Dallas TX 75390 USA;

    Stockholm Univ Dept Biochem & Biophys Sci Life Lab Solna Sweden;

    Stockholm Univ Dept Biochem & Biophys Sci Life Lab Solna Sweden;

    Univ Texas Southwestern Med Ctr Dallas Dept Neurosci Dallas TX 75390 USA;

    Univ Texas Southwestern Med Ctr Dallas Dept Neurosci Dallas TX 75390 USA;

    Harvard Med Sch Blavatnik Inst Dept Biol Chem & Mol Pharmacol Boston MA 02115 USA;

    Stockholm Univ Dept Biochem & Biophys Sci Life Lab Solna Sweden|KTH Royal Inst Technol Swedish ESci Res Ctr Dept Appl Phys Solna Sweden;

    Univ Texas Southwestern Med Ctr Dallas Dept Neurosci Dallas TX 75390 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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