Preprint / Version 2

Open-state structure of veratridine-activated human Nav1.7 reveals the molecular choreography of fast inactivation

This article is a preprint and has not been certified by peer review.

Authors

    XIAO FAN,  
    XIAO FAN
    • Shenzhen Medical Academy of Research and Translation
    Jiaofeng Chen,  
    Jiaofeng Chen
    Lingfeng Xue,  
    Lingfeng Xue
    Huan Wang,  
    Huan Wang
    Tong Wu,  
    Tong Wu
    Xiaoshuang Huang,  
    Xiaoshuang Huang
    • Shenzhen Medical Academy of Research and Translation
    Fangzhou Lu,  
    Fangzhou Lu
    • Shenzhen Medical Academy of Research and Translation
    Xueqin Jin,  
    Xueqin Jin
    Chen Song,  
    Chen Song
    Jian Huang,  
    Jian Huang
    • Shenzhen Medical Academy of Research and Translation
    Nieng Yan
    Nieng Yan
    • Shenzhen Medical Academy of Research and Translation
    • Tsinghua University image/svg+xml
Categories
Biochemistry & Biophysics
Keywords
Voltage gated sodium channel; Open-state; Fast inactivation; Veratridine

Abstract

Almost all the reported cryo-EM structures of eukaryotic voltage-gated sodium (Nav) channels, including those of human Nav1.1-Nav1.8, represent various inactivated states that are characteristic of a non-conductive pore domain (PD) surrounded by voltage-sensing domains (VSDs) in varying up conformations. To capture an open-state Navstructure, we treated purified human Nav1.7 with a natural neurotoxin veratridine (VTD) and solved its cryo-EM structures. Two VTD-bound Nav1.7 complexes were obtained. One, with VTD inserted in the IFM-binding corner (site I), resembles other inactivated structures. The other, wherein VTD traverses the central cavity (site C), represents an activated conformation with the constriction diameter of 8.2 Å at the intracellular gate. Structural analysis reveals the mechanism of action of VTD’s bimodal modulation of Nav channels. More importantly, structural comparison between the open and inactivated states provides advanced molecular insight into the fast inactivation process.

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DOI:

https://doi.org/10.65215/pwqkq726

Submission ID:

1

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Posted

2025-12-04

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How to Cite

FAN, X., Chen, J., Xue, L., Wang, H., Wu, T., Huang, X., Lu, F., Jin, X., Song, C., Huang, J., & Yan, N. (2025). Open-state structure of veratridine-activated human Nav1.7 reveals the molecular choreography of fast inactivation. LangTaoSha Preprint Server. https://doi.org/10.65215/pwqkq726

Declaration of Competing Interests

The authors declare no competing interests to disclose.

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