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

Abstract

Mutational studies have identified part of the S5-S6 loop of voltage-dependent K+ channels (P region) responsible for tetraethylammonium (TEA) block and 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 been identified by mutation-induced alteration in toxin binding, and some of the interaction partners have been identified by mutation of channel residues using mutant cycle analysis. This has provided a general picture for the channel vestibule. Here, we examine the interaction predicted when the scorpion 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 with Asp-386 of the opposing subunit in the channel 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 outer ring of four C-end His-404 residues. For ChTX the interaction with Asp-386 is reduced, but this is compensated by additional non-bonded interactions formed by Tyr-36 and Arg-34. Comparison of calculated energy of interaction of these specific toxin-channel residue pairs with experimental studies reveals good agreement. The similar total calculated energy of interaction is consistent with the similar IC50 for Kv1.3 block by KITX and ChTX. Molecular modeling shows complementarity of the pore model to toxin spatial structures, and contributes to our understanding of the surface topology to the K+ channel outer vestibule.