Engineering a potent and specific blocker of voltage-gated potassium channel Kv1.3, a target for autoimmune diseases
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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Autoimmune diseases occur as a result of an attack by the immune system on the body’s own tissues resulting in damage and dysfunction. There are different types of autoimmune diseases, in which there is a complex and unknown interaction between genetics and the environment. Discover the latest research on autoimmune diseases here.