Unwinding and spiral sliding of S4 and domain rotation of VSD during the electromechanical coupling in Na_v1.7.

ABSTRACT: Voltage-gated sodium (Na_v) channel Na_v1.7 has been targeted for the development of nonaddictive pain killers. Structures of Na_v1.7 in distinct functional states will offer an advanced mechanistic understanding and aid drug discovery. Here we report the cryoelectron microscopy analysis of a human Na_v1.7 variant that, with 11 rationally introduced point mutations, has a markedly right-shifted activation voltage curve with V_1/2 reaching 69 mV. The voltage-sensing domain in the first repeat (VSD_I) in a 2.7-Å resolution structure displays a completely down (deactivated) conformation. Compared to the structure of WT Na_v1.7, three gating charge (GC) residues in VSD_I are transferred to the cytosolic side throug

SUBMITTER: Huang G 

PROVIDER: S-EPMC9388133 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature