ena-STUDY-UNIVERSIDADE DE BRASILIA-14-05-2019-23:46:01:026-187
Trypsin-induced head-to-tail cyclization in a scorpion venom trypsin inhibitor peptide
Peptidase inhibitors (PIs) have been broadly studied due to their wide therapeutic potential. A unique potent trypsin inhibitor from Tityus obscurus scorpion venom was isolated and characterized. ToPI1 has 3806.89 Da, three disulfide bonds and 33 amino acid residues. Although its precursor sequence shares some primary structure similarity with other scorpion venom K + channel blockers, ToPI1 presented low or no activity against the six K + channel subtypes tested. The X-ray structure of ToPI1 complexed with trypsin in association with the mass spectrometry data indicate a sequential set of events: the complex binding with the inhibitor Lys 32 in the S1 pocket, the inhibitor C-terminal residue Ser 33 cleavage and the cyclization via a peptide bond between residues Ile 1 and Lys 32 . Kinetic and thermodynamic characterization of the complex was obtained. In its cyclic form, the inhibitor shares structural similarities with plant cyclotides, such as MCoTI-I and II, which also inhibit trypsin.
Peptidase inhibitors (PIs) have been broadly studied due to their wide therapeutic potential. A unique potent trypsin inhibitor from Tityus obscurus scorpion venom was isolated and characterized. ToPI1 has 3806.89 Da, three disulfide bonds and 33 amino acid residues. Although its precursor sequence shares some primary structure similarity with other scorpion venom K + channel blockers, ToPI1 presented low or no activity against the six K + channel subtypes tested. The X-ray structure of ToPI1 complexed with trypsin in association with the mass spectrometry data indicate a sequential set of events: the complex binding with the inhibitor Lys 32 in the S1 pocket, the inhibitor C-terminal residue Ser 33 cleavage and the cyclization via a peptide bond between residues Ile 1 and Lys 32 . Kinetic and thermodynamic characterization of the complex was obtained. In its cyclic form, the inhibitor shares structural similarities with plant cyclotides, such as MCoTI-I and II, which also inhibit trypsin.