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dc.contributor.authorDaly, Norelle L
dc.contributor.authorThorstholm, Louise
dc.contributor.authorGreenwood, Kathryn P
dc.contributor.authorKing, Gordon J
dc.contributor.authorRosengren, K Johan
dc.contributor.authorHeras, Begona
dc.contributor.authorMartin, Jennifer L
dc.contributor.authorCraik, David J
dc.date.accessioned2018-01-24T02:16:46Z
dc.date.available2018-01-24T02:16:46Z
dc.date.issued2013
dc.identifier.issn0021-9258
dc.identifier.doi10.1074/jbc.M113.528240
dc.identifier.urihttp://hdl.handle.net/10072/171873
dc.description.abstractMCoTI-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.
dc.description.peerreviewedYes
dc.languageEnglish
dc.language.isoeng
dc.publisherThe American Society for Biochemistry and Molecular Biology Inc
dc.relation.ispartofpagefrom36141
dc.relation.ispartofpageto36148
dc.relation.ispartofissue50
dc.relation.ispartofjournalJournal of Biological Chemistry
dc.relation.ispartofvolume288
dc.subject.fieldofresearchChemical sciences
dc.subject.fieldofresearchBiological sciences
dc.subject.fieldofresearchBiochemistry and cell biology not elsewhere classified
dc.subject.fieldofresearchBiomedical and clinical sciences
dc.subject.fieldofresearchcode34
dc.subject.fieldofresearchcode31
dc.subject.fieldofresearchcode310199
dc.subject.fieldofresearchcode32
dc.titleStructural insights into the role of the cyclic backbone in a squash trypsin inhibitor
dc.typeJournal article
dc.type.descriptionC1 - Articles
dc.type.codeC - Journal Articles
gro.hasfulltextNo Full Text
gro.griffith.authorMartin, Jennifer


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