Structural Similarity between Defense Peptide from Wheat and Scorpion Neurotoxin Permits Rational Functional Design [Neurobiology]

March 26th, 2014 by Berkut, A. A., Usmanova, D. R., Peigneur, S., Oparin, P. B., Mineev, K. S., Odintsova, T. I., Tytgat, J., Arseniev, A. S., Grishin, E. V., Vassilevski, A. A.

In this paper we present the spatial structure of the wheat antimicrobial peptide (AMP) Tk-AMP-X2 studied using NMR spectroscopy. This peptide is found to adopt a disulfide-stabilized α-helical hairpin fold and therefore belongs to the α-hairpinin family of plant defense peptides. Based on Tk-AMP-X2 structural similarity to cone snail and scorpion potassium channel blockers, a mutant molecule Tk-hefu and was engineered by incorporating the functionally important residues from κ-hefutoxin 1 onto Tk-AMP-X2 scaffold. The designed peptide contained the so-called essential dyad of amino acid residues significant for channel-blocking activity. Electrophysiological studies showed that while the parent peptide Tk-AMP-X2 did not present any activity against potassium channels, Tk-hefu blocked Kv1.3 channels with similar potency (IC50 ≈35 μM) to κ-hefutoxin 1 (IC50 ≈40 μM). We conclude that α-hairpinins are attractive in their simplicity structural templates, which may be used for functional engineering and drug design.