Molecular modeling of scorpion toxin binding to voltage-gated K+ channels

Mutational studies have identified part of the S5-S6 loop of voltage-depend ent K+ channels (P region) responsible for tetraethylammonium (TEA) block a nd permeation properties. Several scorpion peptide toxins - charybdotoxin ( ChTX), kaliotoxin (KITX), and agitoxin (AgTX) - also block the channel with high affinity and specificity. An interaction surface for the toxins has b een identified by mutation-induced alteration in toxin binding, and some of the interaction partners have been identified by mutation of channel resid ues using mutant cycle analysis. This has provided a general picture for th e channel vestibule. Here, we examine the interaction predicted when the sc orpion toxins are docked onto a molecular model of the K+ channel pore (the Kv1.3 isoform) that we recently proposed [1]. In the optimal alignment of the toxin with the pore, Arg-24 of KITX or AgTX forms a hydrogen bond with the Asp-386 carboxyl of one subunit, and Asn-30 is in immediate contact wit h Asp-386 of the opposing subunit in the channel tetramer. Toxin residues i n proximity to the side chain of Lys-27 (Phe-25, Thr-36, Met-29, and Ser-11 in KITX) interact with the outer ring of four C-end His-404 residues. For ChTX the interaction with Asp-386 is reduced, but this is compensated by ad ditional non-bonded interactions formed by Tyr-36 and Arg-34. Comparison of calculated energy of interaction of these specific toxin-channel residue p airs with experimental studies reveals good agreement. The similar total ca lculated energy of interaction is consistent with the similar IC50 for Kv1. 3 block by KITX and ChTX. Molecular modeling shows complementarity of the p ore model to toxin spatial structures, and contributes to our understanding of the surface topology to the K+ channel outer vestibule.