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Protein Cell. 2017 Jun;8(6):401-438. doi: 10.1007/s13238-017-0372-z. Epub 2017 Feb 1.

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

Huang W1,2,3, Liu M2, Yan SF4, Yan N5,6,7.

Author information

1
State Key Laboratory of Membrane Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing, 100084, China.
2
Beijing Advanced Innovation Center for Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing, 100084, China.
3
Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences and School of Medicine, Tsinghua University, Beijing, 100084, China.
4
Molecular Design and Chemical Biology, Roche Pharma Research and Early Development, Roche Innovation Center Shanghai, Shanghai, 201203, China. frank.yan@outlook.com.
5
State Key Laboratory of Membrane Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing, 100084, China. nyan@tsinghua.edu.cn.
6
Beijing Advanced Innovation Center for Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing, 100084, China. nyan@tsinghua.edu.cn.
7
Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences and School of Medicine, Tsinghua University, Beijing, 100084, China. nyan@tsinghua.edu.cn.

Abstract

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 Nav channels are associated with a variety of channelopathies. More than 1000 disease-related mutations have been identified in Nav channels, with Nav1.1 and Nav1.5 each harboring more than 400 mutations. Nav channels represent major targets for a wide array of neurotoxins and drugs. Atomic structures of Nav channels 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 Nav channels. In this Resource article, we summarized all the reported disease-related mutations in human Nav channels, generated a homologous model of human Nav1.7, and structurally mapped disease-associated mutations. Before the determination of structures of human Nav channels, the analysis presented here serves as the base framework for mechanistic investigation of Nav channelopathies and for potential structure-based drug discovery.

KEYWORDS:

Nav channels; Nav1.7; channelopathy; pain; structure modeling

PMID:
28150151
PMCID:
PMC5445024
DOI:
10.1007/s13238-017-0372-z
[Indexed for MEDLINE]
Free PMC Article

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