A MODEL OF SCORPION TOXIN BINDING TO VOLTAGE-GATED K+ CHANNELS

Mutational studies have identified part of the S5-S6 loop of voltage-d ependent K+ channels (P region) responsible for tetraethylammonium (TE A) block and permeation properties. Several scorpion peptide toxins - charybdotoxin (ChTX), kaliotoxin (KITX), and agitoxin (AgTX) - also bl ock the channel with high affinity and specificity. Here, we examine t he interaction predicted when the toxins are docked onto the molecular model of the K+ channel pore that we recently proposed. Docking with the model of the Kv1.3 channel started by location of Lys-27 side chai n into the central axis of the pore, followed by energy minimization. In the optimal arrangement, Arg-24 of KITX or AgTX forms a hydrogen bo nd with the Asp-386 carboxyl of one subunit, and Asn-30 is in immediat e contact with Asp-386 of the opposing subunit in the tetramer. Toxin residues in proximity to the side chain of Lys-27 (Phe-25, Thr-36, Met -29, and Ser-11 in KITX) interact with the four C-end His-404s. For Ch TX the interaction with Asp-386 is reduced, but this is compensated by additional nonbonded interactions formed by Tyr-36 and Arg-34. Compar ison of calculated energy of interaction of these specific toxin-chann el residues with experimental studies reveals good agreement. The simi lar total calculated energy of interaction is consistent with the simi lar IC50 for Kv1.3 block by KITX and AgTX. Steric contacts of residues in position 380 of the S5-P linker with residues on the upper part of toxins permit reconstruction of the K+ channel outer vestibule walls, which are about 30 Angstrom apart and about 9 Angstrom high. Molecula r modeling shows complementarity of the pore model to toxin spacial st ructures, and supports the proposal that the N-terminal borders of the P regions surround residues of their C-terminal halves.