期刊
SCIENCE
卷 363, 期 6433, 页码 1302-+出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.aav8573
关键词
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资金
- MRC Industrial iCASE Ph.D. studentship award [MR/N017927/1]
- Cystic Fibrosis Foundation [INFIEL17F0]
- Howard Hughes Medical Institute
- Institut national de la sante et de la recherche medicale (Inserm)
- Centre national de la recherche scientifique (CNRS: PEPS-2009/PAGAIE)
- National Institute of Neurological Disorders and Stroke of the National Institutes of Health [R01 NS091352]
- [GM122420]
- MRC [1809238] Funding Source: UKRI
Fast inactivation of voltage-gated sodium (Na-v) channels is essential for electrical signaling, but its mechanism remains poorly understood. Here we determined the structures of a eukaryotic Na-v channel alone and in complex with a lethal alpha-scorpion toxin, AaH2, by electron microscopy, both at 3.5-angstrom resolution. AaH2 wedges into voltage-sensing domain IV (VSD4) to impede fast activation by trapping a deactivated state in which gating charge interactions bridge to the acidic intracellular carboxyl-terminal domain. In the absence of AaH2, the S4 helix of VSD4 undergoes a similar to 13-angstrom translation to unlatch the intracellular fast-inactivation gating machinery. Highlighting the polypharmacology of alpha-scorpion toxins, AaH2 also targets an unanticipated receptor site on VSD1 and a pore glycan adjacent to VSD4. Overall, this work provides key insights into fast inactivation, electromechanical coupling, and pathogenic mutations in Na-v channels.
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