MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge, UK.
Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Nature. 2019 Jan;565(7740):454-459. doi: 10.1038/s41586-018-0832-5. Epub 2019 Jan 2.
Type-A γ-aminobutyric (GABA) receptors are ligand-gated chloride channels with a very rich pharmacology. Some of their modulators, including benzodiazepines and general anaesthetics, are among the most successful drugs in clinical use and are common substances of abuse. Without reliable structural data, the mechanistic basis for the pharmacological modulation of GABA receptors remains largely unknown. Here we report several high-resolution cryo-electron microscopy structures in which the full-length human α1β3γ2L GABA receptor in lipid nanodiscs is bound to the channel-blocker picrotoxin, the competitive antagonist bicuculline, the agonist GABA (γ-aminobutyric acid), and the classical benzodiazepines alprazolam and diazepam. We describe the binding modes and mechanistic effects of these ligands, the closed and desensitized states of the GABA receptor gating cycle, and the basis for allosteric coupling between the extracellular, agonist-binding region and the transmembrane, pore-forming region. This work provides a structural framework in which to integrate previous physiology and pharmacology research and a rational basis for the development of GABA receptor modulators.
A型 γ-氨基丁酸（GABA）受体是配体门控氯离子通道，具有非常丰富的药理学特性。它们的一些调节剂，包括苯二氮䓬类药物和全身麻醉剂，是临床应用中最成功的药物之一，也是常见的滥用物质。由于缺乏可靠的结构数据，GABA 受体的药理学调节机制在很大程度上仍然未知。在这里，我们报告了几个高分辨率的冷冻电子显微镜结构，其中全长人源 α1β3γ2L GABA 受体与脂质纳米盘结合，结合的配体包括通道阻断剂荷包牡丹碱、竞争性拮抗剂印防己毒素、激动剂 GABA（γ-氨基丁酸）以及经典的苯二氮䓬类药物阿普唑仑和地西泮。我们描述了这些配体的结合模式和作用机制、GABA 受体门控循环的关闭和脱敏状态，以及细胞外、激动剂结合区与跨膜、孔形成区之间变构偶联的基础。这项工作提供了一个结构框架，可用于整合以前的生理学和药理学研究，并为 GABA 受体调节剂的开发提供了合理的基础。
