Referenced in: none

Automatically associated channels: Kv1.2

Title: Differential molecular information of maurotoxin peptide recognizing IKCa and Kv1.2 channels explored by computational simulation.

Authors: Hong Yi, Su Qiu, Yingliang Wu, Wenxin Li, Baoshan Wang

Journal, date & volume: , 2011 Jan 25 , 11, 3

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/21262000

Abstract
Scorpion toxins are invaluable tools for ion channel research and are potential drugs for human channelopathies. However, it is still an open task to determine the molecular basis underlying the diverse interactions between toxin peptides and ion channels. The inhibitory peptide Maurotoxin (MTX) recognized the distantly related IK(Ca) and Kv1.2 channel with approximately the same potency and using the same functional residues, their differential binding mechanism remain elusive. In this study, we applied computational methods to explore the differential binding modes of MTX to Kv1.2 and IK(Ca) channels, which would help to understand the diversity of channel-toxin interactions and accelerate the toxin-based drug design.A reasonably stable MTX-IK(Ca) complex was obtained by combining various computational methods and by in-depth comparison with the previous model of the MTX-Kv1.2 complex. Similarly, MTX adopted the β-sheet structure as the interacting surface for binding both channels, with Lys23 occluding the pore. In contrast, the other critical residues Lys27, Lys30, and Tyr32 of MTX adopted distinct interactions when associating with the IK(Ca) channel. In addition, the residues Gln229, Ala230, Ala233, and Thr234 on the IK(Ca) channel turret formed polar and non-polar interactions with MTX, whereas the turret of Kv1.2 was almost not involved in recognizing MTX. In all, the pairs of interacting residues on MTX and the IK(Ca) channel of the bound complex indicated that electrostatic and Van der Waal interactions contributed equally to the formation of a stable MTX-IK(Ca) complex, in contrast to the MTX-Kv1.2 binding that is dominantly mediated by electrostatic forces.Despite sharing similar pharmacological profiles toward both IK(Ca) and Kv1.2 channels, MTX adopted totally diverging modes in the two association processes. All the molecular information unveiled here could not only offer a better understanding about the structural differences between the IK(Ca) and Kv1.2 channels, but also provide novel structural clues that will help in the designing of more selective molecular probes to discriminate between these two channels.