2. Academic Validation
  3. Structural mapping of Nav1.7 antagonists

Structural mapping of Nav1.7 antagonists

  • Nat Commun. 2023 Jun 3;14(1):3224. doi: 10.1038/s41467-023-38942-3.
Qiurong Wu # 1,  Jian Huang # 2,  Xiao Fan # 3,  Kan Wang # 4,  Xueqin Jin # 1,  Gaoxingyu Huang 5 6,  Jiaao Li 1,  Xiaojing Pan 7,  Nieng Yan 8 9 10
Affiliations

Affiliations

  • 1 Beijing Frontier Research Center for Biological Structures, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084, China.
  • 2 Department of Molecular Biology, Princeton University, Princeton, NJ, 08544, USA. jh6493@princeton.edu.
  • 3 Department of Molecular Biology, Princeton University, Princeton, NJ, 08544, USA. xiaof@princeton.edu.
  • 4 Department of Anesthesiology, China-Japan Friendship Hospital, Beijing, 100029, China.
  • 5 Westlake Laboratory of Life Sciences and Biomedicine, Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, 18 Shilongshan Road, Hangzhou, 310024, Zhejiang Province, China.
  • 6 Institute of Biology, Westlake Institute for Advanced Study, 18 Shilongshan Road, Hangzhou, 310024, Zhejiang Province, China.
  • 7 Beijing Frontier Research Center for Biological Structures, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084, China. panxj@tsinghua.edu.cn.
  • 8 Beijing Frontier Research Center for Biological Structures, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084, China. nyan@tsinghua.edu.cn.
  • 9 Department of Molecular Biology, Princeton University, Princeton, NJ, 08544, USA. nyan@tsinghua.edu.cn.
  • 10 Shenzhen Medical Academy of Research and Translation, Guangming District, Shenzhen, 518107, Guangdong Province, China. nyan@tsinghua.edu.cn.
  • # Contributed equally.
PMID: 37270609 DOI: 10.1038/s41467-023-38942-3
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.

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