A new mechanism in potassium channel blockage identified for a scorpion venom peptide

Background: Scorpion venom is a source of ion channel modifier peptides with interesting pharmacologicalproperties. Here, in addition to reporting the structure of a peptide(meuK۲-۲), identified in the Mesobuthuseupeus venom gland, its interaction with Kv۱.۳ channel was also interpreted.Methods: Three-dimensional structure of meuK۲-۲ was generated using MODELLER and I-TASSER,PHYRE۲, Robetta servers. The best model was selected according to Z-score;and considered for furtheroptimization using MD simulation.Interaction of meuK۲-۲ with the Kv۱.۳ channel was also evaluated usingpeptide-protein docking experiments with HADDOCK software, subsequently pose clustering and also, ۱۰۰ns MD simulations using a protein-water system in the NVT ensemble by Gromacs to evaluate the bindinginteraction between meuK۲-۲ and Kv۱.۳.The final docked complexes were then subject to minimization withCHARMM force field and investigated key interacting residues, electrostatic interactions, binding freeenergies, folding pattern, hydrogen bond formation, hydrophobic contacts.Results: ۳-D structure of the meuK۲-۲ is composed of a cysteine-stabilized α-helical and β-sheet(CSα/β)folding.Two key residues and H-bonds are involved in the binding of meuK۲-۲ to Kv۱.۳.In a new mechanismmeuK۲-۲ binds to both turret and pore loop of the channel.The binding of meuK۲-۲ induces someconformational changes to Kv۱.۳. This is followed by occupation of the pore of the channel with the sidechain of a His۹ residue.Altogether blocks the ion permeation pathway.Conclusions: A new mechanism was predicted for channel blocking with meuK۲-۲.Since Kv۱.۳ plays asignificant role in human T cell activation, meuK۲-۲ have a potential for further investigations to develop asa pharmacological tool in treatment of autoimmune diseases.

Keywords:

Mesobuthus eupeus , Venominvformatics , Potassium channel blocker , Homology modeling , Natural peptide