A Model 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. Here, we examine the 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 chain into the central axis of the pore, followed by energy minimization. In the optimal arrangement, 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 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 ChTX the interaction with Asp-386 is reduced, but this is compensated by additional nonbonded interactions formed by Tyr-36 and Arg-34. Comparison of calculated energy of interaction of these specific toxin-channel residues 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 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 Å apart and about 9 Å high. Molecular modeling shows complementarity of the pore model to toxin spacial structures, and supports the proposal that the N-terminal borders of the P regions surround residues of their C-terminal halves.