Insights into the Molecular Inhibition of the Oncogenic Channel K(V)10.1 by Globular Toxins
Por:
Hernandez-Meza, Juan M., Mares-Samano, Sergio, Garduno-Juarez, Ramon
Publicada:
24 may 2021
Resumen:
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 k-hefutoxin 1, all of which described as hKV10.1
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.
Filiaciones:
Hernandez-Meza, Juan M.:
Univ Nacl Autonoma Mexico, Inst Ciencias Fis, Cuernavaca 62210, Morelos, Mexico
Mares-Samano, Sergio:
Univ Nacl Autonoma Mexico, CONACYT Inst Ciencias Fis, Cuernavaca 62210, Morelos, Mexico
Garduno-Juarez, Ramon:
Univ Nacl Autonoma Mexico, Inst Ciencias Fis, Cuernavaca 62210, Morelos, Mexico
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