A new mechanism in potassium channel blockage identified for a scorpion venom peptide
-
Masoumeh Baradaran,1,*
1. Toxicology Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
- Introduction: Scorpion venom is a source of ion channel modifier peptides with interesting pharmacological properties. Here, in addition to reporting the structure of a peptide(meuK2-2), identified in the Mesobuthus eupeus venom gland, its interaction with Kv1.3 channel was also interpreted.
- Methods: Three-dimensional structure of meuK2-2 was generated using MODELLER and I-TASSER,PHYRE2,Robetta servers. The best model was selected according to Z-score;and considered for further optimization using MD simulation.Interaction of meuK2-2 with the Kv1.3 channel was also evaluated using peptide-protein docking experiments with HADDOCK software, subsequently pose clustering and also, 100 ns MD simulations using a protein-water system in the NVT ensemble by Gromacs to evaluate the binding interaction between meuK2-2 and Kv1.3.The final docked complexes were then subject to minimization with CHARMM force field and investigated key interacting residues, electrostatic interactions, binding free energies, folding pattern, hydrogen bond formation, hydrophobic contacts.
- Results: 3-D structure of the meuK2-2 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 meuK2-2 to Kv1.3.In a new mechanism meuK2-2 binds to both turret and pore loop of the channel.The binding of meuK2-2 induces some conformational changes to Kv1.3. This is followed by occupation of the pore of the channel with the side chain of a His9 residue.Altogether blocks the ion permeation pathway.
- Conclusion: A new mechanism was predicted for channel blocking with meuK2-2.Since Kv1.3 plays a significant role in human T cell activation, meuK2-2 have a potential for further investigations to develop as a pharmacological tool in treatment of autoimmune diseases.
- Keywords: Mesobuthus eupeus; Venominvformatics; Potassium channel blocker; Homology modeling; Natural peptide
