Structure of recombinant Leishmania donovani pteridine reductase reveals a disordered active site

Keri L. Barrack, Lindsay B. Tulloch, Lynsey-Ann Burke, Paul K. Fyfe, William N. Hunter

    Research output: Contribution to journalArticlepeer-review

    20 Citations (Scopus)

    Abstract

    Pteridine reductase (PTR1) is a potential target for drug development against parasitic Trypanosoma and Leishmania species, protozoa that are responsible for a range of serious diseases found in tropical and subtropical parts of the world. As part of a structure-based approach to inhibitor development, specifically targeting Leishmania species, well ordered crystals of L. donovani PTR1 were sought to support the characterization of complexes formed with inhibitors. An efficient system for recombinant protein production was prepared and the enzyme was purified and crystallized in an orthorhombic form with ammonium sulfate as the precipitant. Diffraction data were measured to 2.5 angstrom resolution and the structure was solved by molecular replacement. However, a sulfate occupies a phosphate-binding site used by NADPH and occludes cofactor binding. The nicotinamide moiety is a critical component of the active site and without it this part of the structure is disordered. The crystal form obtained under these conditions is therefore unsuitable for the characterization of inhibitor complexes.

    Original languageEnglish
    Pages (from-to)33-37
    Number of pages5
    JournalActa Crystallographica F-Structural Biology and Crystallization Communications
    Volume67
    DOIs
    Publication statusPublished - Jan 2011

    Keywords

    • DRUG-RESISTANCE
    • INHIBITORS
    • DESIGN
    • METABOLISM
    • DISCOVERY
    • COMPLEX
    • BINDING
    • TARGET
    • PTR1

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