Preprint / Version 1

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This article is a preprint and has not been certified by peer review.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 non-conductive pore domain (PD) and voltage-sensing domains (VSDs) activated to varying degrees. To capture an open-state Nav structure, we treated purified human Nav1.7 with 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 a diameter of 8.2 Å at the constriction site of the intracellular gate. Structural analysis reveals the mechanism of action of VTD’s bimodal modulation of Nav channels. More importantly, a comparison between this open state and inactivated structures provides detailed 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

2025-11-18

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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