Key result
A mutant OSK1 toxin blocked the Kv1.3 channel with an IC50 of 0.2 pM, demonstrating >10000-fold greater specificity for Kv1.3 than for Kv1.1 and Kv1.2 channels.
Engineering of the OSK1 toxin created a highly potent and specific blocker for the Kv1.3 channel, a potential target for immunosuppressive therapy.
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Mutant OSK1 provides a potent Kv1.3-selective probe; leaves open its immunosuppressive potential pending in vivo validation.
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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Chen et al. (2012) studied Autoimmune diseases. Mutant OSK1 toxin vs. Wild-type OSK1 was evaluated on Half-maximal inhibitory concentration (IC50). A mutant OSK1 toxin blocked the Kv1.3 channel with an IC50 of 0.2 pM, demonstrating >10000-fold greater specificity for Kv1.3 than for Kv1.1 and Kv1.2 channels.
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