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

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

  • Proc Natl Acad Sci U S A. 2022 Jul 26;119(30):e2208211119. doi: 10.1073/pnas.2208211119.
Xiaoshuang Huang 1 Xueqin Jin 1 Gaoxingyu Huang 2 3 Jian Huang 1 Tong Wu 1 Zhangqiang Li 1 Jiaofeng Chen 1 Fang Kong 1 Xiaojing Pan 1 Nieng Yan 1
Affiliations

Affiliations

  • 1 State Key Laboratory of Membrane Biology, Beijing Advanced Innovation Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.
  • 2 Westlake Laboratory of Life Sciences and Biomedicine, Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou 310024, China.
  • 3 Institute of Biology, Westlake Institute for Advanced Study, Hangzhou 310024, China.
Abstract

The dorsal root ganglia-localized voltage-gated sodium (Nav) channel Nav1.8 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.

Keywords

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

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