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Toxins 2016, 8(4), 115; doi:10.3390/toxins8040115

The Scorpion Toxin Analogue BmKTX-D33H as a Potential Kv1.3 Channel-Selective Immunomodulator for Autoimmune Diseases

State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China
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Academic Editor: Irina Vetter
Received: 23 January 2016 / Revised: 11 April 2016 / Accepted: 12 April 2016 / Published: 19 April 2016
(This article belongs to the Special Issue Animal Toxins and Biological Ion Channels)
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Abstract

The Kv1.3 channel-acting scorpion toxins usually adopt the conserved anti-parallel β-sheet domain as the binding interface, but it remains challenging to discover some highly selective Kv1.3 channel-acting toxins. In this work, we investigated the pharmacological profile of the Kv1.3 channel-acting BmKTX-D33H, a structural analogue of the BmKTX scorpion toxin. Interestingly, BmKTX-D33H, with its conserved anti-parallel β-sheet domain as a Kv1.3 channel-interacting interface, exhibited more than 1000-fold selectivity towards the Kv1.3 channel as compared to other K+ channels (including Kv1.1, Kv1.2, Kv1.7, Kv11.1, KCa2.2, KCa2.3, and KCa3.1). As expected, BmKTX-D33H was found to inhibit the cytokine production and proliferation of both Jurkat cells and human T cells in vitro. It also significantly improved the delayed-type hypersensitivity (DTH) responses, an autoreactive T cell-mediated inflammation in rats. Amino acid sequence alignment and structural analysis strongly suggest that the “evolutionary” Gly11 residue of BmKTX-D33H interacts with the turret domain of Kv1 channels; it appears to be a pivotal amino acid residue with regard to the selectivity of BmKTX-D33H towards the Kv1.3 channel (in comparison with the highly homologous scorpion toxins). Together, our data indicate that BmKTX-D33H is a Kv1.3 channel–specific blocker. Finally, the remarkable selectivity of BmKTX-D33H highlights the great potential of evolutionary-guided peptide drug design in future studies. View Full-Text
Keywords: Kv1.3 channel; BmKTX; scorpion toxin; BmKTX-D33H; ion channel selectivity; autoimmune diseases Kv1.3 channel; BmKTX; scorpion toxin; BmKTX-D33H; ion channel selectivity; autoimmune diseases
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Ye, F.; Hu, Y.; Yu, W.; Xie, Z.; Hu, J.; Cao, Z.; Li, W.; Wu, Y. The Scorpion Toxin Analogue BmKTX-D33H as a Potential Kv1.3 Channel-Selective Immunomodulator for Autoimmune Diseases. Toxins 2016, 8, 115.

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