BioSysBio:abstracts/2007/Mahboobeh Zarrabi

=Simulation of interactions of the κ-hefutoxin1 with the voltage-gated potassium ion channels= Author(s): M.Zarrabi, H.Naderi-Manesh Affiliations: Faculty of Science, Tarbiat Modares University, P.O.Box 14115-175,Tehran, Iran Contact:zarrabi@modares.ac.ir'''

Keywords:simulation,scorpion toxin,potassium channel,interaction'''

The κ-hefutoxin1 adopts a unique three-dimensional fold of two parallel helices linked by two disulfide bridges without any β_sheets. κ-Hefutoxin 1 not only blocks the voltage-gated K-channels, Kv1.3 and Kv1.2, but also slows the activation kinetics of Kv1.3 currents, a novel feature of κ-hefutoxin 1, unlike other scorpion toxins, which are considered solely pore blockers. The recognition of the scorpion toxin κ-hefutoxin1 by the voltage-gated potassium (Kv1) channels, Kv1.1, Kv1.2, and Kv1.3, has been studied by 3D-dock software package. All of the 20 available structures of κ-hefutoxin1 were considered during the simulations, which indicated that the conformation of κ-hefutoxin1 significantly affected both the recognition and the binding between κ-hefutoxin1 and the Kv1 channels. Comparing the highest-frequency structures of κ-hefutoxin1 binding to the Kv1 channels, we found that the Kv1.2 channel, with the highest docking frequencies and the lowest electrostatic interaction energies, was the most favorable for κ-hefutoxin1 binding, whereas Kv1.1 was intermediate, and Kv1.3 was the least favorable one. From the κ-hefutoxin1-Kv1.2 binding model, we identified the critical residues for the recognition of these two proteins. Κ-hefutoxin1 locates around the extracellular mouth of the Kv1 channels, making contacts with its helices. Lys 19, Tyr 5, Arg 6, Trp 9 or Arg 10 in the toxin and residues Asp 402, His 404, Thr 407,Gly 401 and Asp 386 in each subunit of the Kv potassium channel are the key residues for the toxin-channel recognition. Docking results and MD simulations indicated that our three-dimensional models of the toxin-channel complex are reasonable and can be used as a guide for future biological studies such as the rational design of the blocking agents of the Kv1 channels. Moreover, the simulation result demonstrates that the hydrophobic interactions are important in interaction negatively charge toxins with potassium channels.

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