小柯机器人

美国俄勒冈卫生与科学大学Eric Gouaux研究团队发现，冷冻电镜结构揭示GAB_AA受体的原生组装和药理作用。2023年9月20日，国际知名学术期刊《自然》在线发表了这一成果。

研究人员分离出了含有广泛表达的α1亚基的原生小鼠A型γ-氨基丁酸受体（GABA_AR）集合体，并阐明了它们与治疗失眠（唑吡坦（ZOL）和氟拉西泮）和产后抑郁（神经类固醇异丙孕酮（APG））的药物复合物的结构。利用冷冻电镜（cryo-EM）分析和单分子光漂白实验，研究人员发现了大脑中的三种主要结构群：包含两个α1亚基的典型α1β2γ2受体，以及包含一个α1和一个α2或α3亚基的两种组合，其中包含单个α1的受体在跨膜和胞外结构域之间的排列更为紧凑。有趣的是，APG与跨膜α/β亚基界面结合，即使没有添加到样品中也是如此，这揭示了内源性神经类固醇在调节原生GABA_AR中的重要作用。

据介绍，A型γ-氨基丁酸受体（GABA_AR）是大脑中的主要抑制受体，也是多种临床药物的靶点，包括麻醉剂、镇静剂、催眠药和抗抑郁药。然而，人们对GABA_AR药理学的了解一直受阻于19个不同亚基可衍生出的大量五聚体组合以及临床相关受体结构知识的缺乏。

附：英文原文

Title: Cryo-EM structures reveal native GABAA receptor assemblies and pharmacology

Author: Sun, Chang, Zhu, Hongtao, Clark, Sarah, Gouaux, Eric

Issue&Volume: 2023-09-20

Abstract: Type A γ-aminobutyric acid receptors (GABAARs) are the principal inhibitory receptors in the brain and the target of a wide range of clinical agents, including anaesthetics, sedatives, hypnotics and antidepressants1,2,3. However, our understanding of GABAAR pharmacology has been hindered by the vast number of pentameric assemblies that can be derived from 19 different subunits4 and the lack of structural knowledge of clinically relevant receptors. Here, we isolate native murine GABAAR assemblies containing the widely expressed α1 subunit and elucidate their structures in complex with drugs used to treat insomnia (zolpidem (ZOL) and flurazepam) and postpartum depression (the neurosteroid allopregnanolone (APG)). Using cryo-electron microscopy (cryo-EM) analysis and single-molecule photobleaching experiments, we uncover three major structural populations in the brain: the canonical α1β2γ2 receptor containing two α1 subunits, and two assemblies containing one α1 and either an α2 or α3 subunit, in which the single α1-containing receptors feature a more compact arrangement between the transmembrane and extracellular domains. Interestingly, APG is bound at the transmembrane α/β subunit interface, even when not added to the sample, revealing an important role for endogenous neurosteroids in modulating native GABAARs. Together with structurally engaged lipids, neurosteroids produce global conformational changes throughout the receptor that modify the ion channel pore and the binding sites for GABA and insomnia medications. Our data reveal the major α1-containing GABAAR assemblies, bound with endogenous neurosteroid, thus defining a structural landscape from which subtype-specific drugs can be developed.

DOI: 10.1038/s41586-023-06556-w

Source: https://www.nature.com/articles/s41586-023-06556-w

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
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