High-resolution structures of a chitinase complexed with natural product cyclopentapeptide inhibitors: mimicry of carbohydrate substrate

Douglas R. Houston, Kazuro Shiomi, Noriko Arai, Satoshi Omura, Martin G. Peter, Andreas Turberg, Bjornar Synstad, Vincent G. H. Eijsink, Daan M. F. van Aalten, Gregory A. Petsko (Editor)

    Research output: Contribution to journalArticlepeer-review

    87 Citations (Scopus)

    Abstract

    Over the past years, family 18 chitinases have been validated as potential targets for the design of drugs against human pathogens that contain or interact with chitin during their normal life cycles. Thus far, only one potent chitinase inhibitor has been described in detail, the pseudotrisaccharide allosamidin. Recently, however, two potent natural-product cyclopentapeptide chitinase inhibitors, argifin and argadin, were reported. Here, we describe high-resolution crystal structures that reveal the details of the interactions of these cyclopeptides with a family 18 chitinase. The structures are examples of complexes of a carbohydrate-processing enzyme with high-affinity peptide-based inhibitors and show in detail how the peptide backbone and side chains mimic the interactions of the enzyme with chitooligosaccharides. Together with enzymological characterization, the structures explain why argadin shows an order of magnitude stronger inhibition than allosamidin, whereas argifin shows weaker inhibition. The peptides bind to the chitinase in remarkably different ways, which may explain the differences in inhibition constants. The two complexes provide a basis for structure-based design of potent chitinase inhibitors, accessible by standard peptide chemistry.
    Original languageEnglish
    Pages (from-to)9127-9132
    Number of pages6
    JournalProceedings of the National Academy of Sciences of the United States of America
    Volume99
    Issue number14
    DOIs
    Publication statusPublished - 2002

    Keywords

    • Chitinase

    Fingerprint Dive into the research topics of 'High-resolution structures of a chitinase complexed with natural product cyclopentapeptide inhibitors: mimicry of carbohydrate substrate'. Together they form a unique fingerprint.

    Cite this