Structural Basis of Nav1.7 Inhibition by a Gating-Modifier Spider Toxin

• Published in: Cell Vol. 176; no. 4; pp. 702 - 715.e14
• Main Authors: Xu, Hui, Li, Tianbo, Rohou, Alexis, Arthur, Christopher P., Tzakoniati, Foteini, Wong, Evera, Estevez, Alberto, Kugel, Christine, Franke, Yvonne, Chen, Jun, Ciferri, Claudio, Hackos, David H., Koth, Christopher M., Payandeh, Jian
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 07.02.2019
• Subjects: gating model; gating modifier toxin; inhibitor cystine knot; Nav1.7; protoxin II; voltage-gated sodium channel; Nav1.7; protoxin II; inhibitor cystine knot; voltage-gated sodium channel; gating model; gating modifier toxin
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2018.12.018

Voltage-gated sodium (Nav) channels are targets of disease mutations, toxins, and therapeutic drugs. Despite recent advances, the structural basis of voltage sensing, electromechanical coupling, and toxin modulation remains ill-defined. Protoxin-II (ProTx2) from the Peruvian green velvet tarantula is an inhibitor cystine-knot peptide and selective antagonist of the human Nav1.7 channel. Here, we visualize ProTx2 in complex with voltage-sensor domain II (VSD2) from Nav1.7 using X-ray crystallography and cryoelectron microscopy. Membrane partitioning orients ProTx2 for unfettered access to VSD2, where ProTx2 interrogates distinct features of the Nav1.7 receptor site. ProTx2 positions two basic residues into the extracellular vestibule to antagonize S4 gating-charge movement through an electrostatic mechanism. ProTx2 has trapped activated and deactivated states of VSD2, revealing a remarkable ∼10 Å translation of the S4 helix, providing a structural framework for activation gating in voltage-gated ion channels. Finally, our results deliver key templates to design selective Nav channel antagonists. [Display omitted] Spider toxin ProTx2 engages the Nav1.7 channel through a membrane access pathwayThe toxin uses an electrostatic mechanism to oppose voltage sensor domain II activationThe toxin complexes with activated and deactivated states of voltage sensor domain IIA basis for electromechanical coupling in voltage-gated ion channels is revealed Seeing how a spider toxin blocks a sodium channel suggests a structural basis for channel gating and avenues for developing new modulators.