Structural mapping of Na_v1.7 antagonists.

ABSTRACT: Voltage-gated sodium (Na_v) channels are targeted by a number of widely used and investigational drugs for the treatment of epilepsy, arrhythmia, pain, and other disorders. Despite recent advances in structural elucidation of Na_v channels, the binding mode of most Na_v-targeting drugs remains unknown. Here we report high-resolution cryo-EM structures of human Na_v1.7 treated with drugs and lead compounds with representative chemical backbones at resolutions of 2.6-3.2 Å. A binding site beneath the intracellular gate (site BIG) accommodates carbamazepine, bupivacaine, and lacosamide. Unexpectedly, a second molecule of lacosamide plugs into the selectivity filter from the central cavity. Fenestrations are popular sites for various state-dependent drug

SUBMITTER: Wu Q 

PROVIDER: S-EPMC10239435 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature