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研究解析天然甘氨酸受体的结构和组装机制
2021-09-26 14:26

美国俄勒冈健康与科学大学Eric Gouaux研究团队解析天然甘氨酸受体的结构和组装机制。相关论文于2021年9月23日在线发表在《自然》杂志上。

研究人员表示,甘氨酸受体(GlyR)是五聚体,这些"Cys环"受体形成氯渗透通道,在整个中枢神经系统介导快速抑制性信号传递。在脊髓和脑干,GlyR调节运动,并在突变时导致运动障碍。然而,尽管进行了广泛的研究,天然GlyR的化学计量和它们的组装机制仍然不清楚。

研究人员报告了来自猪脊髓和脑干天然GlyR的近原子分辨率结构,揭示了对异构体受体及其主要的4个α亚单位:1个β亚单位化学计量的首次结构分析。在异体五聚体中,β(+)/α(-)界面采用了一种与α(+)/α(-)和α(+)/β(-)界面不同的结构。此外,β亚单位有一个独特的苯丙氨酸残基,该残基位于孔隙内,破坏了典型的印防己毒素部位。

这些结果解释了为什么β亚单位的包括会打破受体的对称性并改变离子通道的药理学。研究人员还发现了不完整的受体复合物,并通过阐明其结构首次揭示了部分组装的α三聚体和α四聚体结构。

附:英文原文

Title: Architecture and assembly mechanism of native glycine receptors

Author: Zhu, Hongtao, Gouaux, Eric

Issue&Volume: 2021-09-23

Abstract: Glycine receptors (GlyRs) are pentameric, ‘Cys-loop’ receptors that form chloride-permeable channels and mediate fast inhibitory signaling throughout the central nervous system1,2. In the spinal cord and brainstem, GlyRs regulate locomotion and cause movement disorders when mutated2,3. However, the stoichiometry of native GlyRs and the mechanism by which they are assembled remain unclear, despite extensive investigation4–8. Here we report near-atomic resolution structures of native GlyRs from porcine spinal cord and brainstem, revealing the first structural insight into heteromeric receptors and their predominant stoichiometry of 4 α subunits:1 β subunit. Within the heteromeric pentamer, the β(+)/α(-) interface adopts a structure that is distinct from the α(+)/α(-) and α(+)/β(-) interfaces. Furthermore, the β subunit harbors a unique phenylalanine residue that resides within the pore and disrupts the canonical picrotoxin site. These results explain why inclusion of the β subunit breaks receptor symmetry and alters ion channel pharmacology. We also find incomplete receptor complexes and, by elucidating their structures, reveal the architectures of partially assembled α trimers and α tetramers for the first time.

DOI: 10.1038/s41586-021-04022-z

Source: https://www.nature.com/articles/s41586-021-04022-z

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
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

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