Work

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

Year: 2025

Type: preprint

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.

DOI: 10.65215/pwqkq726

Authors: XIAO FAN, Jiaofeng Chen, Lingfeng Xue, Huan Wang, Tong Wu, Xiaoshuang Huang, Fangzhou Lu, Xueqin Jin, Chen Song, Jian Huang, Nieng Yan

Institutions: Shenzhen Medical Academy of Research and Translation, Tsinghua University, Peking University

Language: English

Topic: Ion channel regulation and function

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

Open Access status: green

Funders: Princeton University, National Natural Science Foundation of China

Award: G347144111

OpenAlex ID: W4416334586

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