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Potent, multi-target serine protease inhibition achieved by a simplified beta-sheet motif
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2019 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 14, no 1, article id e0210842Article in journal (Refereed) Published
Abstract [en]

Engagement of an extended beta-sheet is a common substrate/inhibitor interaction at the active site of serine proteases and is an important feature of Laskowski mechanism inhibitors that present a substrate-like loop to a target protease. This loop is cleaved but subsequently relegated forming a stable inhibitor/protease complex. Laskowski inhibitors are ubiquitous in nature and are used extensively in serine protease inhibitor design. However, most studies concentrate on introducing new sidechain interactions rather than the direct contributions of the substrate-like beta-sheet to enzyme inhibition. Here we report the crystal structure of an simplified beta-sheet inhibitory motif within the Sunflower Trypsin Inhibitor (SFTI) in complex with trypsin. We show that the intramolecular hydrogen bond network of this SFTI variant (SFTI-TCTR) engages the inhibitor sidechains that would normally interact with a target protease, giving mainchain interactions a more prominent role in complex formation. Despite having reduced sidechain interactions, this SFTI variant is remarkably potent and inhibits a diverse range of serine proteases. Crystal structural analysis and molecular modelling of SFTI-TCTR complexes again indicates an interface dominated by beta-sheet interactions, highlighting the importance of this motif and the adaptability of SFTI as a scaffold for inhibitor design.

Place, publisher, year, edition, pages
Public Library Science , 2019. Vol. 14, no 1, article id e0210842
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Medicinal Chemistry Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-156314DOI: 10.1371/journal.pone.0210842ISI: 000456306400019PubMedID: 30668585OAI: oai:DiVA.org:umu-156314DiVA, id: diva2:1290398
Available from: 2019-02-20 Created: 2019-02-20 Last updated: 2019-02-20Bibliographically approved

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Brattsand, Maria

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