Engineering a potent and specific blocker of voltage-gated potassium channel Kv1.3, a target for autoimmune diseases

Biochemistry
Rong Chen, Shin-Ho Chung

Abstract

A polypeptide toxin extracted from scorpion venom, OSK1, is modified such that its potency is drastically enhanced in blocking one class of voltage-gated potassium channels, Kv1.3, which is a pharmacological target for immunosuppressive therapy. The bound complex of Kv1.3 and OSK1 reveals that one lysine residue of the toxin is in the proximity of another lysine residue on the external vestibule of the channel, just outside of the selectivity filter. This unfavorable electrostatic interaction is eliminated by interchanging the positions of two amino acids in the toxin. The potentials of mean force of the wild-type and mutant OSK1 bound to Kv1.1-Kv1.3 channels are constructed using molecular dynamics, and the half-maximal inhibitory concentration (IC(50)) of each toxin-channel complex is computed. We show that the IC(50) values predicted for three toxins and three channels match closely with experiment. Kv1.3 is half-blocked by 0.2 pM mutant OSK1; it is >10000-fold more specific for this channel than for Kv1.1 and Kv1.2.

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Citations

Jan 12, 2013·Analytical and Bioanalytical Chemistry·Kseniya S KudryashovaAlexey V Feofanov
Jul 17, 2013·Nanoscale Research Letters·Tamsyn A Hilder, Shin-Ho Chung
Oct 14, 2016·Journal of Molecular Modeling·Vinodhkumar VijayakumarGünther H Peters
Mar 8, 2017·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Evelyne Deplazes
Nov 20, 2012·The Journal of Physical Chemistry. B·Dan Gordon, Shin-Ho Chung
Jul 19, 2012·The Journal of Physical Chemistry. B·R VijayarajV Subramanian

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