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Cryo-EM structure of human voltage-gated sodium channel Na(v)1.6

Voltage-gated sodium channel Na(v)1.6 plays a crucial role in neuronal firing in the central nervous system (CNS). Aberrant function of Na(v)1.6 may lead to epilepsy and other neurological disorders. Specific inhibitors of Na(v)1.6 thus have therapeutic potentials. Here we present the cryo-EM struct...

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Autores principales: Fan, Xiao, Huang, Jian, Jin, Xueqin, Yan, Nieng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9945969/
https://www.ncbi.nlm.nih.gov/pubmed/36696443
http://dx.doi.org/10.1073/pnas.2220578120
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author Fan, Xiao
Huang, Jian
Jin, Xueqin
Yan, Nieng
author_facet Fan, Xiao
Huang, Jian
Jin, Xueqin
Yan, Nieng
author_sort Fan, Xiao
collection PubMed
description Voltage-gated sodium channel Na(v)1.6 plays a crucial role in neuronal firing in the central nervous system (CNS). Aberrant function of Na(v)1.6 may lead to epilepsy and other neurological disorders. Specific inhibitors of Na(v)1.6 thus have therapeutic potentials. Here we present the cryo-EM structure of human Na(v)1.6 in the presence of auxiliary subunits β1 and fibroblast growth factor homologous factor 2B (FHF2B) at an overall resolution of 3.1 Å. The overall structure represents an inactivated state with closed pore domain (PD) and all “up” voltage-sensing domains. A conserved carbohydrate–aromatic interaction involving Trp302 and Asn326, together with the β1 subunit, stabilizes the extracellular loop in repeat I. Apart from regular lipids that are resolved in the EM map, an unprecedented Y-shaped density that belongs to an unidentified molecule binds to the PD, revealing a potential site for developing Na(v)1.6-specific blockers. Structural mapping of disease-related Na(v)1.6 mutations provides insights into their pathogenic mechanism.
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spelling pubmed-99459692023-07-25 Cryo-EM structure of human voltage-gated sodium channel Na(v)1.6 Fan, Xiao Huang, Jian Jin, Xueqin Yan, Nieng Proc Natl Acad Sci U S A Biological Sciences Voltage-gated sodium channel Na(v)1.6 plays a crucial role in neuronal firing in the central nervous system (CNS). Aberrant function of Na(v)1.6 may lead to epilepsy and other neurological disorders. Specific inhibitors of Na(v)1.6 thus have therapeutic potentials. Here we present the cryo-EM structure of human Na(v)1.6 in the presence of auxiliary subunits β1 and fibroblast growth factor homologous factor 2B (FHF2B) at an overall resolution of 3.1 Å. The overall structure represents an inactivated state with closed pore domain (PD) and all “up” voltage-sensing domains. A conserved carbohydrate–aromatic interaction involving Trp302 and Asn326, together with the β1 subunit, stabilizes the extracellular loop in repeat I. Apart from regular lipids that are resolved in the EM map, an unprecedented Y-shaped density that belongs to an unidentified molecule binds to the PD, revealing a potential site for developing Na(v)1.6-specific blockers. Structural mapping of disease-related Na(v)1.6 mutations provides insights into their pathogenic mechanism. National Academy of Sciences 2023-01-25 2023-01-31 /pmc/articles/PMC9945969/ /pubmed/36696443 http://dx.doi.org/10.1073/pnas.2220578120 Text en Copyright © 2023 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/This article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle Biological Sciences
Fan, Xiao
Huang, Jian
Jin, Xueqin
Yan, Nieng
Cryo-EM structure of human voltage-gated sodium channel Na(v)1.6
title Cryo-EM structure of human voltage-gated sodium channel Na(v)1.6
title_full Cryo-EM structure of human voltage-gated sodium channel Na(v)1.6
title_fullStr Cryo-EM structure of human voltage-gated sodium channel Na(v)1.6
title_full_unstemmed Cryo-EM structure of human voltage-gated sodium channel Na(v)1.6
title_short Cryo-EM structure of human voltage-gated sodium channel Na(v)1.6
title_sort cryo-em structure of human voltage-gated sodium channel na(v)1.6
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9945969/
https://www.ncbi.nlm.nih.gov/pubmed/36696443
http://dx.doi.org/10.1073/pnas.2220578120
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