Structure of saccharomyces cerevisiae chitinase 1 and screening-based discovery of potent inhibitors

Ramon Hurtado-Guerrero, Daan M. F. van Aalten

    Research output: Contribution to journalArticle

    48 Citations (Scopus)

    Abstract

    Chitinases hydrolyse the ß(1,4)-glycosidic bonds of chitin, an essential fungal cell wall component. Genetic data on a subclass of fungal family 18 chitinases have suggested a role in cell wall morphology. Specific inhibitors of these enzymes would be useful as tools to study their role in cell wall morphogenesis and could possess antifungal properties. Here, we describe the crystallographic structure of a fungal “plant-type” family 18 chitinase, that of Saccharomyces cerevisiae CTS1. The enzyme is active against 4-methylumbelliferyl chitooligosaccharides and displays an unusually low pH optimum for activity. A library screen against ScCTS1 yielded hits with Ki's as low as 3.2 µM. Crystal structures of ScCTS1 in complex with inhibitors from three series reveal striking mimicry of carbohydrate substrate by small aromatic moieties and a pocket that could be further exploited in optimization of these inhibitors.

    Original languageEnglish
    Pages (from-to)589-599
    Number of pages11
    JournalChemistry & Biology
    Volume14
    Issue number5
    DOIs
    Publication statusPublished - 29 May 2007

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