Structure-based assessment of disease- related mutations in human voltage-gated sodium channels

作     者：Weiyun Huang Minhao Liu S. Frank Yan Nieng Yan 

作者机构：State Key Laboratory of Membrane Biology School of Life Sciences and School of Medicine Tsinghua University Beijing 100084 China Beijing Advanced Innovation Center for Structural Biology School of Life Sciences and School of Medicine Tsinghua University Beijing 100084 China Tsinghua-Peking Joint Center for Life Sciences School of Life Sciences and School of Medicine Tsinghua UniversityBeijing 100084 China Molecular Design and Chemical Biology Roche Pharma Research and Early Development Roche Innovation CenterShanghai Shanghai 201203 China 

出 版 物：《Protein & Cell》 (蛋白质与细胞（英文版）)

年 卷 期：2017年第8卷第6期

页      面：401-438页

核心收录：

学科分类：0710[理学-生物学] 090403[农学-农药学(可授农学、理学学位）] 07[理学] 09[农学] 071007[理学-遗传学] 0904[农学-植物保护] 

基　　金：supported by funds from the National Basic Research Program (973 Program) 国家自然科学基金 

主　　题：Nav channels channelopathy Navl.7,structure modeling pain 

摘      要：Voltage-gated sodium （Nav） channels are essential for the rapid upstroke of action potentials and the propa- gation of electrical signals in nerves and muscles. Defects of Nav channels are associated with a variety of channelopathies. More than 1000 disease-related muta- tions have been identified in Nay channels, with Nay1.1 and Nay1.5 each harboring more than 400 mutations. Nay channels represent major targets for a wide array of neurotoxins and drugs. Atomic structures of Nav chan- nels are required to understand their function and dis- ease mechanisms. The recently determined atomic structure of the rabbit voltage-gated calcium （Car） channel Carl.1 provides a template for homology-based structural modeling of the evolutionarily related Nay channels. In this Resource article, we summarized all the reported disease-related mutations in human Nav channels, generated a homologous model of human Nay1.7, and structurally mapped disease-associated mutations. Before the determination of structures of human Nay channels, the analysis presented here serves as the base framework for mechanistic investi- gation of Nav channelopathies and for potential struc- ture-based drug discovery.