Structural basis for high-voltage activation and subtype-specific inhibition of human Na_v1.8.

ABSTRACT: The dorsal root ganglia-localized voltage-gated sodium (Na_v) channel Na_v1.8 represents a promising target for developing next-generation analgesics. A prominent characteristic of Na_v1.8 is the requirement of more depolarized membrane potential for activation. Here we present the cryogenic electron microscopy structures of human Na_v1.8 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 (VSD_I) displays three different conformations. Structure-guided mutagenesis identified the extracellular interface between VSD_I and the pore domain (PD) to be a determinant for the high-voltage dependence of activation. A-803467 was clearly resolved in the central cavi

SUBMITTER: Huang X 

PROVIDER: S-EPMC9335304 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature