Vollum Institute, Oregon Health and Science University, Portland, OR, USA.
Howard Hughes Medical Institute, Oregon Health and Science University, Portland, OR, USA.
Nature. 2021 Nov;599(7885):513-517. doi: 10.1038/s41586-021-04022-z. Epub 2021 Sep 23.
Glycine receptors (GlyRs) are pentameric, 'Cys-loop' receptors that form chloride-permeable channels and mediate fast inhibitory signalling throughout the central nervous system. In the spinal cord and brainstem, GlyRs regulate locomotion and cause movement disorders when mutated. However, the stoichiometry of native GlyRs and the mechanism by which they are assembled remain unclear, despite extensive investigation. Here we report cryo-electron microscopy structures of native GlyRs from pig spinal cord and brainstem, revealing structural insights into heteromeric receptors and their predominant subunit stoichiometry of 4α:1β. 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 contains 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.
甘氨酸受体（GlyRs）是五聚体“Cys 环”受体，形成氯离子通透通道，并在中枢神经系统中介导快速抑制信号。在脊髓和脑干中，GlyRs 调节运动，如果发生突变会引起运动障碍。然而，尽管进行了广泛的研究，天然 GlyRs 的化学计量和它们的组装机制仍不清楚。在这里，我们报告了来自猪脊髓和脑干的天然 GlyRs 的冷冻电子显微镜结构，揭示了异源五聚体受体的结构见解及其主要的亚基化学计量为 4α:1β。在异源五聚体中，β(+)-α(-)界面采用与 α(+)-α(-)和 α(+)-β(-)界面不同的结构。此外，β 亚基包含一个独特的苯丙氨酸残基，位于孔内并破坏了经典的苦毒蕈碱结合位点。这些结果解释了为什么包含β亚基会打破受体对称性并改变离子通道药理学。我们还发现了不完全的受体复合物，并通过阐明它们的结构，揭示了部分组装的α 三聚体和α 四聚体的结构。
