Structure of Staphylococcus aureus adenylosuccinate lyase (PurB) and assessment of its potential as a target for structure-based inhibitor discovery

Paul K. Fyfe, Alice Dawson, Marie-Theres Hutchison, Scott Cameron, William N. Hunter

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    11 Citations (Scopus)

    Abstract

    The medium-resolution structure of adenylosuccinate lyase (PurB) from the bacterial pathogen Staphylococcus aureus in complex with AMP is presented. Oxalate, which is likely to be an artifact of crystallization, has been modelled in the active site and occupies a position close to that where succinate is observed in orthologous structures. PurB catalyzes reactions that support the provision of purines and the control of AMP/fumarate levels. As such, the enzyme is predicted to be essential for the survival of S. aureus and to be a potential therapeutic target. Comparisons of this pathogen PurB with the enzyme from Escherichia coli are presented to allow discussion concerning the enzyme mechanism. Comparisons with human PurB suggest that the close similarity of the active sites would make it difficult to identify species-specific inhibitors for this enyme. However, there are differences in the way that the subunits are assembled into dimers. The distinct subunit-subunit interfaces may provide a potential area to target by exploiting the observation that creation of the enzyme active site is dependent on oligomerization.

    Original languageEnglish
    Pages (from-to)881-888
    Number of pages8
    JournalActa Crystallographica Section D: Biological Crystallography
    Volume66
    DOIs
    Publication statusPublished - Aug 2010

    Keywords

    • PURINE BIOSYNTHETIC-PATHWAY
    • BACILLUS-SUBTILIS
    • ESCHERICHIA-COLI
    • CRYSTAL-STRUCTURE
    • ACTIVE-SITE
    • SUBSTRATE
    • PROTEIN
    • ENZYME
    • ACID
    • VALIDATION

    Cite this

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    title = "Structure of Staphylococcus aureus adenylosuccinate lyase (PurB) and assessment of its potential as a target for structure-based inhibitor discovery",
    abstract = "The medium-resolution structure of adenylosuccinate lyase (PurB) from the bacterial pathogen Staphylococcus aureus in complex with AMP is presented. Oxalate, which is likely to be an artifact of crystallization, has been modelled in the active site and occupies a position close to that where succinate is observed in orthologous structures. PurB catalyzes reactions that support the provision of purines and the control of AMP/fumarate levels. As such, the enzyme is predicted to be essential for the survival of S. aureus and to be a potential therapeutic target. Comparisons of this pathogen PurB with the enzyme from Escherichia coli are presented to allow discussion concerning the enzyme mechanism. Comparisons with human PurB suggest that the close similarity of the active sites would make it difficult to identify species-specific inhibitors for this enyme. However, there are differences in the way that the subunits are assembled into dimers. The distinct subunit-subunit interfaces may provide a potential area to target by exploiting the observation that creation of the enzyme active site is dependent on oligomerization.",
    keywords = "PURINE BIOSYNTHETIC-PATHWAY, BACILLUS-SUBTILIS, ESCHERICHIA-COLI, CRYSTAL-STRUCTURE, ACTIVE-SITE, SUBSTRATE, PROTEIN, ENZYME, ACID, VALIDATION",
    author = "Fyfe, {Paul K.} and Alice Dawson and Marie-Theres Hutchison and Scott Cameron and Hunter, {William N.}",
    year = "2010",
    month = "8",
    doi = "10.1107/S0907444910020081",
    language = "English",
    volume = "66",
    pages = "881--888",
    journal = "Acta Crystallographica Section D: Biological Crystallography",
    issn = "0907-4449",
    publisher = "International Union of Crystallography",

    }

    TY - JOUR

    T1 - Structure of Staphylococcus aureus adenylosuccinate lyase (PurB) and assessment of its potential as a target for structure-based inhibitor discovery

    AU - Fyfe, Paul K.

    AU - Dawson, Alice

    AU - Hutchison, Marie-Theres

    AU - Cameron, Scott

    AU - Hunter, William N.

    PY - 2010/8

    Y1 - 2010/8

    N2 - The medium-resolution structure of adenylosuccinate lyase (PurB) from the bacterial pathogen Staphylococcus aureus in complex with AMP is presented. Oxalate, which is likely to be an artifact of crystallization, has been modelled in the active site and occupies a position close to that where succinate is observed in orthologous structures. PurB catalyzes reactions that support the provision of purines and the control of AMP/fumarate levels. As such, the enzyme is predicted to be essential for the survival of S. aureus and to be a potential therapeutic target. Comparisons of this pathogen PurB with the enzyme from Escherichia coli are presented to allow discussion concerning the enzyme mechanism. Comparisons with human PurB suggest that the close similarity of the active sites would make it difficult to identify species-specific inhibitors for this enyme. However, there are differences in the way that the subunits are assembled into dimers. The distinct subunit-subunit interfaces may provide a potential area to target by exploiting the observation that creation of the enzyme active site is dependent on oligomerization.

    AB - The medium-resolution structure of adenylosuccinate lyase (PurB) from the bacterial pathogen Staphylococcus aureus in complex with AMP is presented. Oxalate, which is likely to be an artifact of crystallization, has been modelled in the active site and occupies a position close to that where succinate is observed in orthologous structures. PurB catalyzes reactions that support the provision of purines and the control of AMP/fumarate levels. As such, the enzyme is predicted to be essential for the survival of S. aureus and to be a potential therapeutic target. Comparisons of this pathogen PurB with the enzyme from Escherichia coli are presented to allow discussion concerning the enzyme mechanism. Comparisons with human PurB suggest that the close similarity of the active sites would make it difficult to identify species-specific inhibitors for this enyme. However, there are differences in the way that the subunits are assembled into dimers. The distinct subunit-subunit interfaces may provide a potential area to target by exploiting the observation that creation of the enzyme active site is dependent on oligomerization.

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    KW - BACILLUS-SUBTILIS

    KW - ESCHERICHIA-COLI

    KW - CRYSTAL-STRUCTURE

    KW - ACTIVE-SITE

    KW - SUBSTRATE

    KW - PROTEIN

    KW - ENZYME

    KW - ACID

    KW - VALIDATION

    U2 - 10.1107/S0907444910020081

    DO - 10.1107/S0907444910020081

    M3 - Article

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    SP - 881

    EP - 888

    JO - Acta Crystallographica Section D: Biological Crystallography

    JF - Acta Crystallographica Section D: Biological Crystallography

    SN - 0907-4449

    ER -