8I5B

Structure of human Nav1.7 in complex with bupivacaine

Summary for 8I5B

• Entry DOI: 10.2210/pdb8i5b/pdb
• EMDB information: 35193
• Descriptor: Sodium channel protein type 9 subunit alpha, Levobupivacaine, Sodium channel subunit beta-1, ... (10 entities in total)
• Functional Keywords: inhibitor complex., membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 293408.44

Authors

Wu, Q.R.,Yan, N. (deposition date: 2023-01-24, release date: 2023-06-14, Last modification date: 2024-10-16)

Primary citation

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

Experimental method

ELECTRON MICROSCOPY (2.7 Å)