Insights into the Molecular Inhibition of the Oncogenic Channel K_V10.1 by Globular Toxins

Inhibition of the expression of the human ether-à-go-go (hEAG1 or hK_V10.1) channel is associated with a dramatic reduction in the growth of several cancerous tumors. The modulation of this channel's activity is a promising target for the development of new anticancer drugs. Although some small molecules have shown inhibitory activity against K_V10.1, their lack of specificity has prevented their use in humans. In vitro studies have recently identified a limited number of peptide toxins with proven specificity in their hK_V10.1 channel inhibitory effect. These peptide toxins have become desirable candidates to use as lead compounds to design more potent and specific hK_V10.1 inhibitors. However, the currently available studies lack the atomic resolution needed to characterize the molecular features that favor their binding to hK_V10.1. In this work, we present the first attempt to locate the possible hK_V10.1 binding sites of the animal peptide toxins APETx4, Aa1a, Ap1a, and k-hefutoxin 1, all of which described as hK_V10.1 inhibitors. Our studies incorporated homology modeling to construct a robust three-dimensional (3D) model of hK_V10.1, applied protein docking, and multiscale molecular dynamics techniques to reveal in atomic resolution the toxin-channel interactions. Our approach suggests that some peptide toxins bind in the outer vestibule surrounding the pore of hK_V10.1; it also identified the channel residues Met397 and Asp398 as possible anchors that stabilize the binding of the evaluated toxins. Finally, a description of the possible mechanism for inhibition and gating is presented.