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  • Structural insights into the role of the cyclic backbone in a squash trypsin inhibitor.

Structural insights into the role of the cyclic backbone in a squash trypsin inhibitor.

The Journal of biological chemistry (2013-10-31)
Norelle L Daly, Louise Thorstholm, Kathryn P Greenwood, Gordon J King, K Johan Rosengren, Begoña Heras, Jennifer L Martin, David J Craik
ABSTRACT

MCoTI-II is a head-to-tail cyclic peptide with potent trypsin inhibitory activity and, on the basis of its exceptional proteolytic stability, is a valuable template for the design of novel drug leads. Insights into inhibitor dynamics and interactions with biological targets are critical for drug design studies, particularly for protease targets. Here, we show that the cyclization and active site loops of MCoTI-II are flexible in solution, but when bound to trypsin, the active site loop converges to a single well defined conformation. This finding of reduced flexibility on binding is in contrast to a recent study on the homologous peptide MCoTI-I, which suggested that regions of the peptide are more flexible upon binding to trypsin. We provide a possible explanation for this discrepancy based on degradation of the complex over time. Our study also unexpectedly shows that the cyclization loop, not present in acyclic homologues, facilitates potent trypsin inhibitory activity by engaging in direct binding interactions with trypsin.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Trypsin Acetylated from bovine pancreas, Type V-S, ≥8,500 BAEE units/mg protein (biuret)
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Trypsin from bovine pancreas, essentially salt-free, lyophilized powder, ≥9,000 BAEE units/mg protein, BioReagent, suitable for cell culture
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Trypsin from bovine pancreas, Type I, ~10,000 BAEE units/mg protein
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Trypsin from bovine pancreas, ≥2,500 USP units/mg solid, meets USP testing specifications
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Trypsin from bovine pancreas, suitable for protein sequencing, lyophilized powder
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Trypsin from bovine pancreas, Type XI, lyophilized powder, ≥6,000 BAEE units/mg protein
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Trypsin from bovine pancreas, TPCK Treated, essentially salt-free, lyophilized powder, ≥10,000 BAEE units/mg protein
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Trypsin from bovine pancreas, TPCK Treated, essentially salt-free, lyophilized powder, ≥10,000 BAEE units/mg protein
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Trypsin from human pancreas, salt-free, lyophilized powder, vial of ≥1,000 BAEE units
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Trypsin from bovine pancreas, powder, ≥7,500 BAEE units/mg solid
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Trypsin from porcine pancreas, ~1500 U/mg
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Trypsin from porcine pancreas, lyophilized powder, BioReagent, suitable for cell culture, 1,000-2,000 BAEE units/mg solid
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