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

    Author(s)
    Daly, Norelle L
    Thorstholm, Louise
    Greenwood, Kathryn P
    King, Gordon J
    Rosengren, K Johan
    Heras, Begona
    Martin, Jennifer L
    Craik, David J
    Griffith University Author(s)
    Martin, Jennifer
    King, Gordon
    Year published
    2013
    Metadata
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    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 ...
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    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.
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    Journal Title
    Journal of Biological Chemistry
    Volume
    288
    Issue
    50
    DOI
    https://doi.org/10.1074/jbc.M113.528240
    Subject
    Chemical sciences
    Biological sciences
    Biochemistry and cell biology not elsewhere classified
    Biomedical and clinical sciences
    Publication URI
    http://hdl.handle.net/10072/171873
    Collection
    • Journal articles

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