Structure-based assessment of disease-related mutations in human voltage-gated sodium channels.
Voltage-gated sodium (Nav) channels are essential for the rapid upstroke of action potentials and the propagation of electrical signals in nerves and muscles. Defects of Navchannels are associated with a variety of channelopathies. More than 1000 disease-related mutations have been identified in Navchannels, with Nav1.1 and Nav1.5 each harboring more than 400 mutations. Navchannels represent major targets for a wide array of neurotoxins and drugs. Atomic structures of Navchannels are required to understand their function and disease mechanisms. The recently determined atomic structure of the rabbit voltage-gated calcium (Cav) channel Cav1.1 provides a template for homology-based structural modeling of the evolutionarily related Navchannels. In this Resource article, we summarized all the reported disease-related mutations in human Navchannels, generated a homologous model of human Nav1.7, and structurally mapped disease-associated mutations. Before the determination of structures of human Navchannels, the analysis presented here serves as the base framework for mechanistic investigation of Navchannelopathies and for potential structure-based drug discovery.
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 University, Beijing, 100084, China.
Weiyun
W
Huang
Beijing Advanced Innovation Center for Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing, 100084, China.
Minhao
M
Liu
Molecular Design and Chemical Biology, Roche Pharma Research and Early Development, Roche Innovation Center Shanghai, Shanghai, 201203, China. frank.yan@outlook.com.
S Frank
SF
Yan
State Key Laboratory of Membrane Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing, 100084, China. nyan@tsinghua.edu.cn.|Beijing Advanced Innovation Center for Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing, 100084, China. nyan@tsinghua.edu.cn.|Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences and School of Medicine, Tsinghua University, Beijing, 100084, China. nyan@tsinghua.edu.cn.
Nieng
N
Yan
D000818:Animals; D020746:Calcium Channels, L-Type / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D053447:Channelopathies / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009154:Mutation; D062550:NAV1.1 Voltage-Gated Sodium Channel / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D062556:NAV1.7 Voltage-Gated Sodium Channel / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000072417:Protein Domains; D011817:Rabbits; D013329:Structure-Activity Relationship
D020746:Calcium Channels, L-Type; D062550:NAV1.1 Voltage-Gated Sodium Channel; D062554:NAV1.5 Voltage-Gated Sodium Channel; D062556:NAV1.7 Voltage-Gated Sodium Channel; C568242:SCN1A protein, human; C568320:SCN5A protein, human; C486866:SCN9A protein, human
Nav channels; Nav1.7; channelopathy; pain; structure modeling