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.
Highlights
The voltage-gated Kv1.3 potassium channel is a well-recognized functional marker and attractive pharmacological target for treating autoimmune diseases [1,2,3,4,5]
We investigated in detail the pharmacological profile of BmKTX-D33H
In comparison with the highly homologous ADWX-1 and other scorpion toxins, the “unique” selectivity of BmKTX-D33H towards the Kv1.3 channel implies a functional evolution of the different amino acid residues among the structurally related scorpion toxins
Summary
The voltage-gated Kv1.3 potassium channel is a well-recognized functional marker and attractive pharmacological target for treating autoimmune diseases [1,2,3,4,5]. Based on the interactions between scorpion toxins and potassium channels, a great effort has been made to find scorpion toxin peptides selectively acting on the Kv1.3 channel using molecular screening and design strategies. Toxins, the “unique” selectivity of BmKTX-D33H towards the Kv1.3 channel implies a functional evolution of the different amino acid residues among the structurally related scorpion toxins. This aspect might be key to the discovery of novel peptide drugs that selectively target the Kv1.3 channel
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