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Papers of the Week

Papers: 9 Feb 2019 - 15 Feb 2019

Animal Studies

2019 03 22




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


Clairfeuille T, Cloake A, Infield DT, Llongueras JP, Arthur CP, Li Z R, Jian Y, Martin-Eauclaire M-F, Bougis PE, Ciferri C, Ahern CA, Bosmans F, Hackos DH, Rohou A, Payandeh J
Science. 2019 03 22; 363(6433).
PMID: 30733386.


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-A resolution. AaH2 wedges into voltage-sensor domain IV (VSD4) to impede fast activation by trapping a deactivated state in which gating charge interactions bridge to the acidic intracellular C-terminal domain. In the absence of AaH2, the S4 helix of VSD4 undergoes a ~13-Å 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.