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

• DOI: 10.1073/pnas.2208211119
• Publication Date: 2022-07-19T17:53:42Z
• Authors: Xiaoshuang Huang; Xueqin Jin; Gaoxingyu Huang; Jian Huang; Tong Wu; Zhangqiang Li; Jiaofeng Chen; Fang Kong; Xiaojing Pan; Nieng Yan
• Keywords: Voltage-Gated Sodium Channel Blockers; 0303 health sciences; 03 medical and health sciences; Aniline Compounds; Allosteric Regulation; Protein Domains; Cryoelectron Microscopy; NAV1.7 Voltage-Gated Sodium Channel; Humans; Biological Sciences; Furans; Membrane Potentials

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