Laverty Duncan, Thomas Philip, Field Martin, Andersen Ole J, Gold Matthew G, Biggin Philip C, Gielen Marc, Smart Trevor G
Department of Neuroscience, Physiology & Pharmacology, University College London, London, UK.
Department of Biochemistry, University of Oxford, Oxford, UK.
Nat Struct Mol Biol. 2017 Nov;24(11):977-985. doi: 10.1038/nsmb.3477. Epub 2017 Oct 2.
γ-Aminobutyric acid receptors (GABARs) 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 GABARs 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 GABAR function requires high-resolution structures. Here we present the first atomic structures of a GABAR 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 GABARs in neurological disorders.
γ-氨基丁酸受体（GABARs）对于控制大脑的兴奋性至关重要。众多由受体功能障碍导致的神经精神疾病凸显了这一点。大多数天然GABARs的一个关键组成部分是α亚基。其跨膜结构域是许多调节剂的作用靶点，包括影响焦虑、应激和抑郁的内源性脑甾体，以及治疗药物，如全身麻醉剂。了解GABAR功能调节的基础需要高分辨率结构。在此，我们展示了分辨率为2.8埃的GABAR嵌合体的首个原子结构，包括与增强和抑制性神经甾体结合的结构。这些结构定义了这些调节剂与α亚基跨膜结构域相关的新变构结合位点。我们的研究结果将有助于利用神经甾体进行治疗药物设计，以调节神经疾病中的GABARs。
