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人类电压门控钠离子通道 Na1.6 的冷冻电镜结构

Cryo-EM structure of human voltage-gated sodium channel Na1.6.

机构信息

Department of Molecular Biology, Princeton University, Princeton, NJ 08544.

State Key Laboratory of Membrane Biology, Beijing Frontier Research Center for Biological Structures, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.

出版信息

Proc Natl Acad Sci U S A. 2023 Jan 31;120(5):e2220578120. doi: 10.1073/pnas.2220578120. Epub 2023 Jan 25.

DOI:10.1073/pnas.2220578120
PMID:36696443
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9945969/
Abstract

Voltage-gated sodium channel Na1.6 plays a crucial role in neuronal firing in the central nervous system (CNS). Aberrant function of Na1.6 may lead to epilepsy and other neurological disorders. Specific inhibitors of Na1.6 thus have therapeutic potentials. Here we present the cryo-EM structure of human Na1.6 in the presence of auxiliary subunits β1 and fibroblast growth factor homologous factor 2B (FHF2B) at an overall resolution of 3.1 Å. The overall structure represents an inactivated state with closed pore domain (PD) and all "up" voltage-sensing domains. A conserved carbohydrate-aromatic interaction involving Trp302 and Asn326, together with the β1 subunit, stabilizes the extracellular loop in repeat I. Apart from regular lipids that are resolved in the EM map, an unprecedented Y-shaped density that belongs to an unidentified molecule binds to the PD, revealing a potential site for developing Na1.6-specific blockers. Structural mapping of disease-related Na1.6 mutations provides insights into their pathogenic mechanism.

摘要

电压门控钠离子通道 Na1.6 在中枢神经系统 (CNS) 的神经元放电中起着至关重要的作用。Na1.6 的功能异常可能导致癫痫和其他神经紊乱。因此，Na1.6 的特异性抑制剂具有治疗潜力。在这里，我们展示了在辅助亚基 β1 和成纤维细胞生长因子同源因子 2B (FHF2B) 存在下，人类 Na1.6 的冷冻电镜结构，整体分辨率为 3.1 Å。整体结构代表一种失活状态，具有闭合的孔域 (PD) 和所有“向上”的电压感应域。涉及色氨酸 302 和天冬酰胺 326 的保守碳水化合物-芳香族相互作用，以及 β1 亚基，稳定了重复 I 中的细胞外环。除了在 EM 图谱中解析出的常规脂质外，还存在一个前所未有的 Y 形密度，属于一个未识别的分子，它与 PD 结合，揭示了开发 Na1.6 特异性阻滞剂的潜在位点。与疾病相关的 Na1.6 突变的结构映射提供了对其致病机制的深入了解。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d0c1/9945969/ab1392771b8d/pnas.2220578120fig04.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d0c1/9945969/a385ff4b04ac/pnas.2220578120fig01.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d0c1/9945969/8773f4c355f6/pnas.2220578120fig02.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d0c1/9945969/fddbadb7821e/pnas.2220578120fig03.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d0c1/9945969/ab1392771b8d/pnas.2220578120fig04.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d0c1/9945969/a385ff4b04ac/pnas.2220578120fig01.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d0c1/9945969/8773f4c355f6/pnas.2220578120fig02.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d0c1/9945969/fddbadb7821e/pnas.2220578120fig03.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d0c1/9945969/ab1392771b8d/pnas.2220578120fig04.jpg

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