PubMed 27311819

Referenced in Channelpedia wiki pages of: none

Automatically associated channels: Nav1 , Nav1.7

Title: Interaction of Tarantula Venom Peptide ProTx-II with Lipid Membranes is a Prerequisite for its Inhibition of Human Voltage-gated Sodium Channel NaV1.7.

Authors: Sónia Troeira Henriques, Evelyne Deplazes, Nicole Lawrence, Olivier Cheneval, Stephanie Chaousis, Marco Inserra, Panumart Thongyoo, Glenn F King, Alan E Mark, Irina Vetter, David J Craik, Christina I Schroeder

Journal, date & volume: J. Biol. Chem., 2016 Jun 16 , ,

PubMed link:

ProTx-II is a disulfide-rich peptide toxin from tarantula venom able to inhibit the human voltage-gated sodium channel 1.7 (hNaV1.7), a channel reported to be involved in nociception, and thus it might have potential as a pain therapeutic. ProTx-II acts by binding to the membrane-embedded voltage sensor domain of hNaV1.7, but the precise peptide channel-binding site and the importance of membrane binding on the inhibitory activity of ProTx-II remain unknown. In this study, we examined the structure and membrane-binding properties of ProTx-II and several analogues using NMR spectroscopy, surface plasmon resonance, fluorescence spectroscopy, and molecular dynamics simulations. Our results show a direct correlation between ProTx-II membrane binding affinity and its potency as an hNaV1.7 channel inhibitor. The data support a model whereby a hydrophobic patch on the ProTx-II surface anchors the molecule at the cell surface in a position that optimizes interaction of the peptide with the binding site on the voltage sensor domain. This is the first study to demonstrate that binding of ProTx-II to the lipid membrane is directly linked to its potency as an hNaV1.7 channel inhibitor.