Structural mapping of Nav1.7 antagonists

Qiurong Wu, Jian Huang (), Xiao Fan (), Kan Wang, Xueqin Jin, Gaoxingyu Huang, Jiaao Li, Xiaojing Pan () and Nieng Yan ()
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Qiurong Wu: School of Life Sciences, Tsinghua University
Jian Huang: Princeton University
Xiao Fan: Princeton University
Kan Wang: China-Japan Friendship Hospital
Xueqin Jin: School of Life Sciences, Tsinghua University
Gaoxingyu Huang: School of Life Sciences, Westlake University
Jiaao Li: School of Life Sciences, Tsinghua University
Xiaojing Pan: School of Life Sciences, Tsinghua University
Nieng Yan: School of Life Sciences, Tsinghua University

Nature Communications, 2023, vol. 14, issue 1, 1-10

Abstract: Abstract Voltage-gated sodium (Nav) 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 Nav channels, the binding mode of most Nav-targeting drugs remains unknown. Here we report high-resolution cryo-EM structures of human Nav1.7 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 Nav channels summarized from the present and previous structures.

Date: 2023
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DOI: 10.1038/s41467-023-38942-3

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