Abstract
The main purpose of this report is to investigate the structural property and new potential function of PPTI (Pseudocerastes Persicus Trypsin Inhibitor), a kunitz-type protein with inhibitory effect against trypsin proteolytic activity. Besides kunitz-type serine protease inhibitors, PPTI shows clear-cut similarities with dendrotoxins (DTXs), the other kunitz-type protein subfamily. The most important reason is the presence of functionally important residues of DTXs at correspondingly the same positions in PPTI. As such, we proposed the new ability of PPTI for inhibiting voltage-gated potassium channels and consequently its dual functionality. At first, we determined the solution structure of PPTI via Nuclear Magnetic Resonance (NMR) spectroscopy. Then by homology modeling, we constructed the model structure of trypsin-PPTI complex to confirm the same interaction pattern as trypsin-BPTI at complex interface. Finally, by Brownian dynamics (BD) simulations of PPTI NMR derived ensemble structure as ligand against homology model of human Kv1.1 potassium channel as receptor, we evaluated the potential DTX-like activity of PPTI. The results of our study support the proposed dual functionality of PPTI.
Highlights
Kunitz-type proteins are one of the most-studied protein families due to their diverse physiological functions and stable conformation
The best solved structures derived from solution Nuclear Magnetic Resonance (NMR) spectroscopy confirmed the presence of the motif structure known as kunitz domain in PPTI
The both helical parts are brought in close contact with each other via the C7-C57 disulfide bond, and the α-helix in C-terminal part is located over the β-sheet motif via the C32-C50 disulfide bond
Summary
Kunitz-type proteins are one of the most-studied protein families due to their diverse physiological functions and stable conformation Members of this protein family are small globular proteins (about 60 amino acid residues in length) with native compact conformation and distinct arrangement of secondary structure motifs, known as kunitz domain [1]. Their overall conformation is stabilized via three intra-chain disulfide bonds with highly conserved pattern of C1-C6, C2-C4, and C3-C5 [2,3,4].
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