Structural basis for high-voltage activation and subtype-specific inhibition of human Nav1.8

Xiaoshuang Huang, Xueqin Jin, Gaoxingyu Huang, Jian Huang, Tong Wu, Zhangqiang Li, Jiaofeng Chen, Fang Kong, Xiaojing Pan, Nieng Yan

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

The dorsal root ganglia-localized voltage-gated sodium (Nav) channelNav1.8 represents a promising target for developing next-generation analgesics. A prominent characteristic of Nav1.8 is the requirement of more depolarized membrane potential for activation. Here we present the cryogenic electron microscopy structures of human Nav1.8 alone and bound to a selective pore blocker, A-803467, at overall resolutions of 2.7 to 3.2 Å. The first voltage-sensing domain (VSDI) displays three different conformations. Structure-guided mutagenesis identified the extracellular interface between VSDI and the pore domain (PD) to be a determinant for the high-voltage dependence of activation. A-803467 was clearly resolved in the central cavity of the PD, clenching S6IV. Our structure-guided functional characterizations show that two nonligand binding residues, Thr397 on S6I and Gly1406 on S6III, allosterically modulate the channel's sensitivity to A-803467. Comparison of available structures of human Nav channels suggests the extracellular loop region to be a potential site for developing subtype-specific pore-blocking biologics.

Original languageEnglish (US)
Article numbere2208211119
JournalProceedings of the National Academy of Sciences of the United States of America
Volume119
Issue number30
DOIs
StatePublished - Jul 26 2022
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • General

Keywords

  • cryo-EM structure
  • electromechanical coupling
  • Nav1.8
  • subtype-specific Nav blocker
  • voltage sensing

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