γ-Aminobutyric acid receptors (GABAARs) are vital for controlling excitability in the brain. This is emphasized by the numerous neuropsychiatric disorders that result from receptor dysfunction. A critical component of most native GABAARs is the α subunit. Its transmembrane domain is the target for many modulators, including endogenous brain neurosteroids that impact anxiety, stress and depression, and for therapeutic drugs, such as general anesthetics. Understanding the basis for the modulation of GABAAR function requires high-resolution structures. Here we present the first atomic structures of a GABAAR chimera at 2.8-Å resolution, including those bound with potentiating and inhibitory neurosteroids. These structures define new allosteric binding sites for these modulators that are associated with the α-subunit transmembrane domain. Our findings will enable the exploitation of neurosteroids for therapeutic drug design to regulate GABAARs in neurological disorders.

中文翻译：

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GABAA 受体嵌合体的晶体结构揭示了新的内源性神经类固醇结合位点。

γ-氨基丁酸受体 (GABAAR) 对于控制大脑的兴奋性至关重要。受体功能障碍导致的众多神经精神疾病强调了这一点。大多数天然 GABAAR 的一个关键组成部分是 α 亚基。它的跨膜结构域是许多调节剂的靶标，包括影响焦虑、压力和抑郁的内源性脑神经甾体，以及全身麻醉药等治疗药物。了解 GABAAR 功能调制的基础需要高分辨率结构。在这里，我们展示了 GABAAR 嵌合体的第一个原子结构，分辨率为 2.8-Å，包括那些与增强和抑制性神经类固醇结合的原子结构。这些结构为这些调节剂定义了新的变构结合位点，这些调节剂与 α-亚基跨膜结构域相关。