title: 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.
authors.affiliation: Research School of Biology, Australian National University, Canberra, ACT 0200, Australia. rong.chen@anu.edu.au
authors.forename: Rong
authors.initials: R
authors.lastname: Chen
authors.forename: Shin-Ho
authors.initials: SH
authors.lastname: Chung
mesh_terms: D001327:Autoimmune Diseases / Q000188:drug therapy*; D001665:Binding Sites; D051664:Kv1.3 Potassium Channel / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D015202:Protein Engineering; D012604:Scorpion Venoms / Q000737:chemistry* / Q000235:genetics; D014118:Toxins, Biological / Q000737:chemistry*
chemical_list: D051664:Kv1.3 Potassium Channel; C104504:OSK1 toxin, Orthochirus scrobiculosus; D012604:Scorpion Venoms; D014118:Toxins, Biological