A potent and Kv1.3-selective analogue of the scorpion toxin HsTX1 as a potential therapeutic for autoimmune diseases

Rashid, M, Huq, R, Tanner, M, Chhabra, S, Khoo, K, Estrada, R, Dhawan, V, Chauhan, S, Pennington, M, Beeton, C, Norton, R and Kuyucak, S 2014, 'A potent and Kv1.3-selective analogue of the scorpion toxin HsTX1 as a potential therapeutic for autoimmune diseases', Scientific Reports, vol. 4, 4509, pp. 1-9.


Document type: Journal Article
Collection: Journal Articles

Title A potent and Kv1.3-selective analogue of the scorpion toxin HsTX1 as a potential therapeutic for autoimmune diseases
Author(s) Rashid, M
Huq, R
Tanner, M
Chhabra, S
Khoo, K
Estrada, R
Dhawan, V
Chauhan, S
Pennington, M
Beeton, C
Norton, R
Kuyucak, S
Year 2014
Journal name Scientific Reports
Volume number 4
Article Number 4509
Start page 1
End page 9
Total pages 9
Publisher Nature
Abstract HsTX1 toxin, from the scorpion Heterometrus spinnifer, is a 34-residue, C-terminally amidated peptide cross-linked by four disulfide bridges. Here we describe new HsTX1 analogues with an Ala, Phe, Val or Abu substitution at position 14. Complexes of HsTX1 with the voltage-gated potassium channels Kv1.3 and Kv1.1 were created using docking and molecular dynamics simulations, then umbrella sampling simulations were performed to construct the potential of mean force (PMF) of the ligand and calculate the corresponding binding free energy for the most stable configuration. The PMF method predicted that the R14A mutation in HsTX1 would yield a > 2â euro ...kcal/mol gain for the Kv1.3/Kv1.1 selectivity free energy relative to the wild-type peptide. Functional assays confirmed the predicted selectivity gain for HsTX1[R14A] and HsTX1[R14Abu], with an affinity for Kv1.3 in the low picomolar range and a selectivity of more than 2,000-fold for Kv1.3 over Kv1.1. This remarkable potency and selectivity for Kv1.3, which is significantly up-regulated in activated effector memory cells in humans, suggest that these analogues represent valuable leads in the development of therapeutics for autoimmune diseases.
Subject Biomolecular Modelling and Design
Keyword(s) peptide fragment
potassium channel blocking agent
potassium channel Kv1.1
potassium channel Kv1.3
protein binding
scorpion venom
TX1 toxin
Heterometrus spinnifer
DOI - identifier 10.1038/srep04509
Copyright notice © 2014 Creative Commons Attribution
ISSN 2045-2322
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