Structural basis of α-scorpion toxin action on Na v channels.

Autor: Clairfeuille T; Department of Structural Biology, Genentech Inc., South San Francisco, CA, USA., Cloake A; Department of Structural Biology, Genentech Inc., South San Francisco, CA, USA.; Department of Physics, University of Oxford, Oxford OX1 3PU, UK., Infield DT; Department of Molecular Physiology and Biophysics, The University of Iowa, Iowa City, IA, USA., Llongueras JP; Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA., Arthur CP; Department of Structural Biology, Genentech Inc., South San Francisco, CA, USA., Li ZR; Department of Biomolecular Resources, Genentech Inc., South San Francisco, CA, USA., Jian Y; Department of Neuroscience, Genentech Inc., South San Francisco, CA, USA., Martin-Eauclaire MF; Aix Marseille Université, CNRS, LNC, UMR 7291, 13003 Marseille, France., Bougis PE; Aix Marseille Université, CNRS, LNC, UMR 7291, 13003 Marseille, France., Ciferri C; Department of Structural Biology, Genentech Inc., South San Francisco, CA, USA., Ahern CA; 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., Bosmans F; 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., Hackos DH; 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., Rohou A; 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., Payandeh J; 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.
Jazyk: angličtina
Zdroj: Science (New York, N.Y.) [Science] 2019 Mar 22; Vol. 363 (6433). Date of Electronic Publication: 2019 Feb 07.
DOI: 10.1126/science.aav8573
Abstrakt: 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 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 Na v channels.
(Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
Databáze: MEDLINE
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