Structural mapping of Na<sub>v</sub>1.7 antagonists.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 37270609.
- Also identified by DOI 10.1038/s41467-023-38942-3 and PMC identifier 10239435.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
Voltage-gated sodium (Na<sub>v</sub>) 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<sub>v</sub> channels, the binding mode of most Na<sub>v</sub>-targeting drugs remains unknown. Here we report high-resolution cryo-EM structures of human Na<sub>v</sub>1.7 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 drugs. We show that vinpocetine, a synthetic derivative of a vinca alkaloid, and hardwickiic acid, a natural product with antinociceptive effect, bind to the III-IV fenestration, while vixotrigine, an analgesic candidate, penetrates the IV-I fenestration of the pore domain. Our results permit building a 3D structural map for known drug-binding sites on Na<sub>v</sub> channels summarized from the present and previous structures.
Medical subject headings
- Carbamazepine
- Voltage-Gated Sodium Channel Blockers