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-Structure paper
タイトル | Structural basis of α-scorpion toxin action on Na channels. |
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ジャーナル・号・ページ | Science, Vol. 363, Issue 6433, Year 2019 |
掲載日 | 2019年3月22日 |
著者 | Thomas Clairfeuille / Alexander Cloake / Daniel T Infield / José P Llongueras / Christopher P Arthur / Zhong Rong Li / Yuwen Jian / Marie-France Martin-Eauclaire / Pierre E Bougis / Claudio Ciferri / Christopher A Ahern / Frank Bosmans / David H Hackos / Alexis Rohou / Jian Payandeh / |
PubMed 要旨 | Fast inactivation of voltage-gated sodium (Na) channels is essential for electrical signaling, but its mechanism remains poorly understood. Here we determined the structures of a eukaryotic Na ...Fast inactivation of voltage-gated sodium (Na) channels is essential for electrical signaling, but its mechanism remains poorly understood. Here we determined the structures of a eukaryotic Na 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 channels. |
リンク | Science / PubMed:30733386 |
手法 | EM (単粒子) |
解像度 | 3.4 - 3.5 Å |
構造データ | |
化合物 | ChemComp-NAG: ChemComp-Y01: ChemComp-76F: ChemComp-LHG: ChemComp-AJP: |
由来 |
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キーワード | MEMBRANE PROTEIN / Sodium channel / scorpion toxin / electrical signaling / fast inactivation |