7DTD

Voltage-gated sodium channel Nav1.1 and beta4

Summary for 7DTD

• Entry DOI: 10.2210/pdb7dtd/pdb
• EMDB information: 30851
• Descriptor: Sodium channel subunit beta-4, Sodium channel protein type 1 subunit alpha, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (4 entities in total)
• Functional Keywords: voltage-gated sodium channel, membrane protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 260226.76

Authors

Yan, N.,Pan, X.,Li, Z.,Huang, G. (deposition date: 2021-01-04, release date: 2021-04-07, Last modification date: 2024-11-13)

Primary citation

Pan, X.,Li, Z.,Jin, X.,Zhao, Y.,Huang, G.,Huang, X.,Shen, Z.,Cao, Y.,Dong, M.,Lei, J.,Yan, N.
Comparative structural analysis of human Na v 1.1 and Na v 1.5 reveals mutational hotspots for sodium channelopathies.
Proc.Natl.Acad.Sci.USA, 118:-, 2021

PubMed 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.

PubMed: 33712547
DOI: 10.1073/pnas.2100066118

Experimental method

ELECTRON MICROSCOPY (3.3 Å)