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Structural Basis of Nav1.7 Inhibition by a Gating-Modifier Spider Toxin.
Cell. 2019 02 07; 176(4):702-715.e14.Cell

Abstract

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.

Authors+Show Affiliations

Department of Structural Biology, Genentech, South San Francisco, CA 94080, USA.Department of Biochemical and Cellular Pharmacology, Genentech, South San Francisco, CA 94080, USA. Electronic address: li.tianbo@gene.com.Department of Structural Biology, Genentech, South San Francisco, CA 94080, USA. Electronic address: rohou.alexis@gene.com.Department of Structural Biology, Genentech, South San Francisco, CA 94080, USA.Department of Structural Biology, Genentech, South San Francisco, CA 94080, USA.Department of Neuroscience, Genentech, South San Francisco, CA 94080, USA.Department of Structural Biology, Genentech, South San Francisco, CA 94080, USA.Department of Biomolecular Resources, Genentech, South San Francisco, CA 94080, USA.Department of Biomolecular Resources, Genentech, South San Francisco, CA 94080, USA.Department of Biochemical and Cellular Pharmacology, Genentech, South San Francisco, CA 94080, USA.Department of Structural Biology, Genentech, South San Francisco, CA 94080, USA.Department of Neuroscience, Genentech, South San Francisco, CA 94080, USA. Electronic address: hackos.david@gene.com.Department of Structural Biology, Genentech, South San Francisco, CA 94080, USA. Electronic address: koth.christopher@gene.com.Department of Structural Biology, Genentech, South San Francisco, CA 94080, USA. Electronic address: payandeh.jian@gene.com.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

30661758

Citation

Xu, Hui, et al. "Structural Basis of Nav1.7 Inhibition By a Gating-Modifier Spider Toxin." Cell, vol. 176, no. 4, 2019, pp. 702-715.e14.
Xu H, Li T, Rohou A, et al. Structural Basis of Nav1.7 Inhibition by a Gating-Modifier Spider Toxin. Cell. 2019;176(4):702-715.e14.
Xu, H., Li, T., Rohou, A., Arthur, C. P., Tzakoniati, F., Wong, E., Estevez, A., Kugel, C., Franke, Y., Chen, J., Ciferri, C., Hackos, D. H., Koth, C. M., & Payandeh, J. (2019). Structural Basis of Nav1.7 Inhibition by a Gating-Modifier Spider Toxin. Cell, 176(4), 702-e14. https://doi.org/10.1016/j.cell.2018.12.018
Xu H, et al. Structural Basis of Nav1.7 Inhibition By a Gating-Modifier Spider Toxin. Cell. 2019 02 7;176(4):702-715.e14. PubMed PMID: 30661758.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Structural Basis of Nav1.7 Inhibition by a Gating-Modifier Spider Toxin. AU - Xu,Hui, AU - Li,Tianbo, AU - Rohou,Alexis, AU - Arthur,Christopher P, AU - Tzakoniati,Foteini, AU - Wong,Evera, AU - Estevez,Alberto, AU - Kugel,Christine, AU - Franke,Yvonne, AU - Chen,Jun, AU - Ciferri,Claudio, AU - Hackos,David H, AU - Koth,Christopher M, AU - Payandeh,Jian, Y1 - 2019/01/17/ PY - 2018/07/02/received PY - 2018/09/11/revised PY - 2018/12/11/accepted PY - 2019/1/22/pubmed PY - 2019/12/4/medline PY - 2019/1/22/entrez KW - Nav1.7 KW - gating model KW - gating modifier toxin KW - inhibitor cystine knot KW - protoxin II KW - voltage-gated sodium channel SP - 702 EP - 715.e14 JF - Cell JO - Cell VL - 176 IS - 4 N2 - 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. SN - 1097-4172 UR - https://www.unboundmedicine.com/medline/citation/30661758/Structural_Basis_of_Nav1_7_Inhibition_by_a_Gating_Modifier_Spider_Toxin_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0092-8674(18)31632-5 DB - PRIME DP - Unbound Medicine ER -