美国南加州大学Vadim Cherezov和美国slac国家加速器实验室Cornelius Gati团队在研究中取得进展。他们揭示了代谢型γ-氨基丁酸受体（GABAB）激活的结构基础。该研究于2020年6月 17日在线发表于《自然》杂志。
在本研究中，研究人员解析了人全长GB1-GB2异源二聚体的四种冷冻电镜结构：一种为无载脂蛋白活性形式、两种激动剂结合中间态形式和一种活性形式的结构，活性形式为异二聚体与激动剂和阳性变构调节剂结合。这些结构揭示出实质性的差异，这解释了GABAB独特激活机制的复杂运动基础。
该研究结果表明，GB1与激动剂结合导致其维纳斯捕蝇夹结构域关闭，引发一系列过渡：首先沿跨膜螺旋6重新排列并使两个跨膜结构域紧密接触，最终通过以下方式在GB2跨膜结构域中诱导构象重排：一种类似杠杆的机制来启动下游信号。该活性状态通过结合跨膜二聚化界面处的正变构调节剂而稳定。
据悉，代谢型GABAB参与调控中枢神经系统中的突触反应，并与神经心理疾病如成瘾以及精神病有关。GABAB属于C类G蛋白偶联受体，其功能中心包含专一的异二聚体，该异二聚体由GB1和GB2亚基组成。每个亚基都具有一个胞外维纳斯捕蝇夹结构域，该结构域与典型的七次跨膜结构域相连。
附：英文原文
Title: Structural basis of the activation of a metabotropic GABA receptor
Author: Hamidreza Shaye, Andrii Ishchenko, Jordy Homing Lam, Gye Won Han, Li Xue, Philippe Rondard, Jean-Philippe Pin, Vsevolod Katritch, Cornelius Gati, Vadim Cherezov
Issue&Volume: 2020-06-17
Abstract: Metabotropic γ-aminobutyric acid receptors (GABAB) are involved in the modulation of synaptic responses in the central nervous system and have been implicated in neuropsychological conditions that range from addiction to psychosis1. GABAB belongs to class C of the G-protein-coupled receptors, and its functional entity comprises an obligate heterodimer that is composed of the GB1 and GB2 subunits2. Each subunit possesses an extracellular Venus flytrap domain, which is connected to a canonical seven-transmembrane domain. Here we present four cryo-electron microscopy structures of the human full-length GB1–GB2 heterodimer: one structure of its inactive apo state, two intermediate agonist-bound forms and an active form in which the heterodimer is bound to an agonist and a positive allosteric modulator. The structures reveal substantial differences, which shed light on the complex motions that underlie the unique activation mechanism of GABAB. Our results show that agonist binding leads to the closure of the Venus flytrap domain of GB1, triggering a series of transitions, first rearranging and bringing the two transmembrane domains into close contact along transmembrane helix 6 and ultimately inducing conformational rearrangements in the GB2 transmembrane domain via a lever-like mechanism to initiate downstream signalling. This active state is stabilized by a positive allosteric modulator binding at the transmembrane dimerization interface.
DOI: 10.1038/s41586-020-2408-4
Source: https://www.nature.com/articles/s41586-020-2408-4
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/
投稿链接：http://www.nature.com/authors/submit_manuscript.html
本期文章：《自然》：Online/在线发表
