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Science. 2019 Mar 22;363(6433). pii: eaav8573. doi: 10.1126/science.aav8573. Epub 2019 Feb 7.

Structural basis of α-scorpion toxin action on Nav channels.

Author information

1
Department of Structural Biology, Genentech Inc., South San Francisco, CA, USA.
2
Department of Physics, University of Oxford, Oxford OX1 3PU, UK.
3
Department of Molecular Physiology and Biophysics, The University of Iowa, Iowa City, IA, USA.
4
Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
5
Department of Biomolecular Resources, Genentech Inc., South San Francisco, CA, USA.
6
Department of Neuroscience, Genentech Inc., South San Francisco, CA, USA.
7
Aix Marseille Université, CNRS, LNC, UMR 7291, 13003 Marseille, France.
8
Department of Molecular Physiology and Biophysics, The University of Iowa, Iowa City, IA, USA. christopher-ahern@uiowa.edu frank.bosmans@ugent.be hackos.david@gene.com rohou.alexis@gene.com payandeh.jian@gene.com.
9
Department of Basic and Applied Medical Sciences, Ghent University, 9000 Ghent, Belgium. christopher-ahern@uiowa.edu frank.bosmans@ugent.be hackos.david@gene.com rohou.alexis@gene.com payandeh.jian@gene.com.
10
Department of Neuroscience, Genentech Inc., South San Francisco, CA, USA. christopher-ahern@uiowa.edu frank.bosmans@ugent.be hackos.david@gene.com rohou.alexis@gene.com payandeh.jian@gene.com.
11
Department of Structural Biology, Genentech Inc., South San Francisco, CA, USA. christopher-ahern@uiowa.edu frank.bosmans@ugent.be hackos.david@gene.com rohou.alexis@gene.com payandeh.jian@gene.com.
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Contributed equally

Abstract

Fast inactivation of voltage-gated sodium (Nav) channels is essential for electrical signaling, but its mechanism remains poorly understood. Here we determined the structures of a eukaryotic Nav channel alone and in complex with a lethal α-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 ~13-angstrom translation to unlatch the intracellular fast-inactivation gating machinery. Highlighting the polypharmacology of α-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 Nav channels.

Comment in

PMID:
30733386
DOI:
10.1126/science.aav8573

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