Abstract
The 34-residue polypeptide maurotoxin (MTx) isolated from scorpion venoms selectively inhibits the current of the voltage-gated potassium channel Kv1.2 by occluding the ion conduction pathway. Here using molecular dynamics simulation as a docking method, the binding modes of MTx to three closely related channels (Kv1.1, Kv1.2 and Kv1.3) are examined. We show that MTx forms more favorable electrostatic interactions with the outer vestibule of Kv1.2 compared to Kv1.1 and Kv1.3, consistent with the selectivity of MTx for Kv1.2 over Kv1.1 and Kv1.3 observed experimentally. One salt bridge in the bound complex of MTx-Kv1.2 forms and breaks in a simulation period of 20ns, suggesting the dynamic nature of toxin-channel interactions. The toxin selectivity likely arises from the differences in the shape of the channel outer vestibule, giving rise to distinct orientations of MTx on block. Potential of mean force calculations show that MTx blocks Kv1.1, Kv1.2 and Kv1.3 with an IC50 value of 6 µM, 0.6nM and 18 µM, respectively.
Highlights
Various short peptides isolated from venoms of poisonous creatures, such as scorpions, bees, snakes, cone snails, and sea anemones, inhibit K+ and other cationic channels by physically occluding the ion conduction pathway
Several mutants of the toxin ShK isolated from the sea anemone have been developed as selective blockers of the voltage-gated K+ channel Kv1.3, which is a target for immunosuppression [2]
A harmonic force is applied if the distance between the side-chain nitrogen of Lys23 and the carbonyl group of Gly376 is above the upper boundary of the distance restraint
Summary
Various short peptides isolated from venoms of poisonous creatures, such as scorpions, bees, snakes, cone snails, and sea anemones, inhibit K+ and other cationic channels by physically occluding the ion conduction pathway. The backbone of these peptide toxins is stabilized by several disulfide bridges [1]. The secondary structure of the toxins is frequently characterized by an a-helix and a double- or triple-strand anti-parallel b-sheet. These toxins have found various potential applications in pharmaceutics as well as physiological studies of ion channels. The synthetic form of the v-conotoxin MVIIA, which is a voltagegated calcium channel blocker, has been approved to treat severe pain [3]
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