Cryo-EM structure of human voltage-gated sodium channel Nav1.6

被引：27
作者：
Fan, Xiao [1 ]
Huang, Jian [1 ]
Jin, Xueqin [2 ]
Yan, Nieng [1 ,2 ]
机构：
[1] Princeton Univ, Dept Mol Biol, Princeton, NJ 08544 USA
[2] Tsinghua Univ, Beijing Frontier Res Ctr Biol Struct, Tsinghua Peking Joint Ctr Life Sci, Sch Life Sci, Beijing 100084, Peoples R China
来源：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2023年 / 120卷 / 05期
关键词：
Nav1; 6; ion channel; epilepsy; cryo-EM; ACTION-POTENTIAL INITIATION; FACTOR HOMOLOGOUS FACTOR; EPILEPTIC ENCEPHALOPATHY; BETA-SUBUNITS; NA(V)1.6; SCN8A; NEURONS; MUTATIONS; CURRENTS; COMPLEX;
D O I：
10.1073/pnas.2220578120
中图分类号：
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号：
07 ; 0710 ; 09 ;
摘要：
Voltage-gated sodium channel Nav1.6 plays a crucial role in neuronal firing in the central nervous system (CNS). Aberrant function of Nav1.6 may lead to epilepsy and other neu-rological disorders. Specific inhibitors of Nav1.6 thus have therapeutic potentials. Here we present the cryo-EM structure of human Nav1.6 in the presence of auxiliary subunits & beta;1 and fibroblast growth factor homologous factor 2B (FHF2B) at an overall resolution of 3.1 & ANGS;. 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 & beta;1 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 Nav1.6-specific blockers. Structural mapping of disease-related Nav1.6 mutations provides insights into their pathogenic mechanism.
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页数：7
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