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

Abstract

Inhibition of the expression of the human ether-a-go-go (hEAG1 or hK V 10.1) 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 V 10.1, 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 V 10.1 channel inhibitory effect. These peptide toxins have become desirable candidates to use as lead compounds to design more potent and specific hK V 10.1 inhibitors. However, the currently available studies lack the atomic resolution needed to characterize the molecular features that favor their binding to hK V 10.1. In this work, we present the first attempt to locate the possible hK V 10.1 binding sites of the animal peptide toxins APETx4, Aa1a, Ap1a, and khefutoxin 1, all of which described as hK V 10.1 inhibitors. Our studies incorporated homology modeling to construct a robust three-dimensional (3D) model of hK V 10.1, 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 V 10.1; 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.

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“…techniques. The results obtained have shown that APETx4 is endowed with multiple binding sites and its inhibitory effect is likely due to induced steric effects that prevent the contact of the extracellular loop in the channel with its voltage sensor domain, thus stabilizing the channel structure in the deep closed state [38].…”

“…More recent studies have been directed to reveal the APETx4–K V 10.1 interactions in an atomic resolution, using protein docking and multiscale molecular dynamics techniques. The results obtained have shown that APETx4 is endowed with multiple binding sites and its inhibitory effect is likely due to induced steric effects that prevent the contact of the extracellular loop in the channel with its voltage sensor domain, thus stabilizing the channel structure in the deep closed state [ 38 ].…”