Fast inhibitory neurotransmission in the brain is principally mediated by the neurotransmitter GABA (γ-aminobutyric acid) and its synaptic target, the type A GABA receptor (GABAA receptor). Dysfunction of this receptor results in neurological disorders and mental illnesses including epilepsy, anxiety and insomnia. The GABAA receptor is also a prolific target for therapeutic, illicit and recreational drugs, including benzodiazepines, barbiturates, anaesthetics and ethanol. Here we present high-resolution cryo-electron microscopy structures of the human α1β2γ2 GABAA receptor, the predominant isoform in the adult brain, in complex with GABA and the benzodiazepine site antagonist flumazenil, the first-line clinical treatment for benzodiazepine overdose. The receptor architecture reveals unique heteromeric interactions for this important class of inhibitory neurotransmitter receptor. This work provides a template for understanding receptor modulation by GABA and benzodiazepines, and will assist rational approaches to therapeutic targeting of this receptor for neurological disorders and mental illness.The cryo-electron microscopy structure of the type A GABA receptor bound to GABA and the benzodiazepine site antagonist flumazenil reveals structural mechanisms that underlie intersubunit interactions and ligand selectivity of the receptor.

中文翻译：

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人类突触 GABAA 受体的结构

大脑中的快速抑制性神经传递主要由神经递质 GABA（γ-氨基丁酸）及其突触靶点 A 型 GABA 受体（GABAA 受体）介导。这种受体的功能障碍会导致神经系统疾病和精神疾病，包括癫痫、焦虑和失眠。GABAA 受体也是治疗性、非法和娱乐性药物（包括苯二氮卓类、巴比妥类、麻醉剂和乙醇）的多产靶点。在这里，我们展示了人 α1β2γ2 GABAA 受体的高分辨率冷冻电子显微镜结构，成人大脑中的主要同种型，与 GABA 和苯二氮卓位点拮抗剂氟马西尼复合，苯二氮卓类药物过量的一线临床治疗。受体结构揭示了这一重要类别的抑制性神经递质受体的独特异聚相​​互作用。这项工作为理解 GABA 和苯二氮卓类的受体调节提供了一个模板，并将有助于为神经障碍和精神疾病治疗靶向该受体的合理方法。 与 GABA 和苯二氮卓结合的 A 型 GABA 受体的冷冻电子显微镜结构位点拮抗剂氟马西尼揭示了作为受体亚基间相互作用和配体选择性基础的结构机制。