Most general anaesthetics and classical benzodiazepine drugs act through positive modulation of γ-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.

中文翻译：

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全身麻醉药和苯二氮卓类药物的共同结构机制

大多数全身麻醉剂和经典的苯二氮卓类药物通过正向调节 γ-氨基丁酸 A 型 (GABA A ) 受体来抑制大脑中的神经元活动 1 – 5 。然而，缺乏关于全身麻醉剂生理受体部位机制的直接结构信息。在这里，我们展示了与静脉麻醉剂、苯二氮卓类药物和抑制性调节剂结合的 GABA A 受体的低温电子显微镜结构。这些结构在脂质环境中得到解决，并辅以电生理学和分子动力学模拟。与麻醉剂苯巴比妥、依托咪酯和丙泊酚复合的 GABA A 受体结构揭示了不同的和常见的跨膜结合位点，这些位点部分由苯二氮卓类药物地西泮共享。GABA A 受体与苯二氮卓类配体结合的结构确定了地西泮的额外膜结合位点，并提出了氟马西尼逆转麻醉剂的变构机制。这项研究为了解药理学上多样化的临床必需药物如何通过重叠和不同的机制发挥作用以增强大脑中的抑制信号传导提供了基础。与静脉麻醉剂和苯二氮卓类药物结合的 GABA A 受体的冷冻电镜结构揭示了共同和不同的跨膜结合位点，并表明麻醉剂的作用机制与苯二氮卓类药物的作用机制部分重叠。