Comparative structural analysis of human Na1.1 and Na1.5 reveals mutational hotspots for sodium channelopathies. Author Xiaojing Pan, Zhangqiang Li, Xueqin Jin, Yanyu Zhao, Gaoxingyu Huang, Xiaoshuang Huang, Zilin Shen, Yong Cao, Mengqiu Dong, Jianlin Lei, Nieng Yan Publication Year 2021 Type Journal Article Abstract Among the nine subtypes of human voltage-gated sodium (Na) channels, the brain and cardiac isoforms, Na1.1 and Na1.5, each carry more than 400 missense mutations respectively associated with epilepsy and cardiac disorders. High-resolution structures are required for structure-function relationship dissection of the disease variants. We report the cryo-EM structures of the full-length human Na1.1-β4 complex at 3.3 Å resolution here and the Na1.5-E1784K variant in the accompanying paper. Up to 341 and 261 disease-related missense mutations in Na1.1 and Na1.5, respectively, are resolved. Comparative structural analysis reveals several clusters of disease mutations that are common to both Na1.1 and Na1.5. Among these, the majority of mutations on the extracellular loops above the pore domain and the supporting segments for the selectivity filter may impair structural integrity, while those on the pore domain and the voltage-sensing domains mostly interfere with electromechanical coupling and fast inactivation. Our systematic structural delineation of these mutations provides important insight into their pathogenic mechanism, which will facilitate the development of precise therapeutic interventions against various sodium channelopathies. Keywords Structure-Activity Relationship, Humans, Mutation, Models, Molecular, Protein Conformation, Protein Subunits, Cryoelectron Microscopy, Channelopathies, NAV1.1 Voltage-Gated Sodium Channel, NAV1.5 Voltage-Gated Sodium Channel Journal Proc Natl Acad Sci U S A Volume 118 Issue 11 Date Published 2021 Mar 16 ISSN Number 1091-6490 DOI 10.1073/pnas.2100066118 Alternate Journal Proc Natl Acad Sci U S A PMCID PMC7980448 PMID 33712547 PubMedPubMed CentralGoogle ScholarBibTeXEndNote X3 XML