8J4F

Structure of human Nav1.7 in complex with Hardwickii acid

8J4F の概要

• エントリーDOI: 10.2210/pdb8j4f/pdb
• EMDBエントリー: 35975
• 分子名称: Sodium channel protein type 9 subunit alpha, Sodium channel subunit beta-1, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (9 entities in total)
• 機能のキーワード: inhibitor complex., membrane protein
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 268610.84

構造登録者

Wu, Q.R.,Yan, N. (登録日: 2023-04-19, 公開日: 2023-06-14, 最終更新日: 2024-10-30)

主引用文献

Wu, Q.,Huang, J.,Fan, X.,Wang, K.,Jin, X.,Huang, G.,Li, J.,Pan, X.,Yan, N.
Structural mapping of Na v 1.7 antagonists.
Nat Commun, 14:3224-3224, 2023

PubMed Abstract: Voltage-gated sodium (Na) 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 channels, the binding mode of most Na-targeting drugs remains unknown. Here we report high-resolution cryo-EM structures of human Na1.7 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 channels summarized from the present and previous structures.

PubMed: 37270609
DOI: 10.1038/s41467-023-38942-3

実験手法

ELECTRON MICROSCOPY (3 Å)