Geobacillus stearothermophilus 6-phosphogluconate dehydrogenase complexed with 6-phosphogluconate

Scott Cameron, Viviane P. Martini, Jorge Iulek, William N. Hunter

    Research output: Contribution to journalArticle

    4 Citations (Scopus)

    Abstract

    Two crystal structures of recombinant Geobacillus stearothermophilus 6-phosphogluconate dehydrogenase (Gs6PDH) in complex with the substrate 6-phosphogluconate have been determined at medium resolution. Gs6PDH shares significant sequence identity and structural similarity with the enzymes from Lactococcus lactis, sheep liver and the protozoan parasite Trypanosoma brucei, for which a range of structures have previously been reported. Comparisons indicate that amino-acid sequence conservation is more pronounced in the two domains that contribute to the architecture of the active site, namely the N-terminal and C-terminal domains, compared with the central domain, which is primarily involved in the subunit-subunit associations required to form a stable dimer. The active-site residues are highly conserved, as are the interactions with the 6-phosphogluconate. There is interest in 6PDH as a potential drug target for the protozoan parasite T. brucei, the pathogen responsible for African sleeping sickness. The recombinant T. brucei enzyme has proven to be recalcitrant to enzyme-ligand studies and a surrogate protein might offer new opportunities to investigate and characterize 6PDH inhibitors. The high degree of structural similarity, efficient level of expression and straightforward crystallization conditions mean that Gs6PDH may prove to be an appropriate model system for structure-based inhibitor design targeting the enzyme from Trypanosoma species.

    Original languageEnglish
    Pages (from-to)450-454
    Number of pages5
    JournalActa Crystallographica F-Structural Biology and Crystallization Communications
    Volume65
    DOIs
    Publication statusPublished - May 2009

    Keywords

    • PENTOSE-PHOSPHATE PATHWAY
    • TRYPANOSOMA-BRUCEI
    • SUBSTRATE-BINDING
    • ENZYME
    • SPECIFICITY
    • DIFFRACTION
    • MECHANISM
    • COENZYME
    • QUALITY
    • ANALOGS

    Cite this

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    title = "Geobacillus stearothermophilus 6-phosphogluconate dehydrogenase complexed with 6-phosphogluconate",
    abstract = "Two crystal structures of recombinant Geobacillus stearothermophilus 6-phosphogluconate dehydrogenase (Gs6PDH) in complex with the substrate 6-phosphogluconate have been determined at medium resolution. Gs6PDH shares significant sequence identity and structural similarity with the enzymes from Lactococcus lactis, sheep liver and the protozoan parasite Trypanosoma brucei, for which a range of structures have previously been reported. Comparisons indicate that amino-acid sequence conservation is more pronounced in the two domains that contribute to the architecture of the active site, namely the N-terminal and C-terminal domains, compared with the central domain, which is primarily involved in the subunit-subunit associations required to form a stable dimer. The active-site residues are highly conserved, as are the interactions with the 6-phosphogluconate. There is interest in 6PDH as a potential drug target for the protozoan parasite T. brucei, the pathogen responsible for African sleeping sickness. The recombinant T. brucei enzyme has proven to be recalcitrant to enzyme-ligand studies and a surrogate protein might offer new opportunities to investigate and characterize 6PDH inhibitors. The high degree of structural similarity, efficient level of expression and straightforward crystallization conditions mean that Gs6PDH may prove to be an appropriate model system for structure-based inhibitor design targeting the enzyme from Trypanosoma species.",
    keywords = "PENTOSE-PHOSPHATE PATHWAY, TRYPANOSOMA-BRUCEI, SUBSTRATE-BINDING, ENZYME, SPECIFICITY, DIFFRACTION, MECHANISM, COENZYME, QUALITY, ANALOGS",
    author = "Scott Cameron and Martini, {Viviane P.} and Jorge Iulek and Hunter, {William N.}",
    year = "2009",
    month = "5",
    doi = "10.1107/S1744309109012767",
    language = "English",
    volume = "65",
    pages = "450--454",
    journal = "Acta Crystallographica F-Structural Biology and Crystallization Communications",
    issn = "1744-3091",
    publisher = "International Union of Crystallography",

    }

    Geobacillus stearothermophilus 6-phosphogluconate dehydrogenase complexed with 6-phosphogluconate. / Cameron, Scott; Martini, Viviane P.; Iulek, Jorge; Hunter, William N.

    In: Acta Crystallographica F-Structural Biology and Crystallization Communications, Vol. 65, 05.2009, p. 450-454.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - Geobacillus stearothermophilus 6-phosphogluconate dehydrogenase complexed with 6-phosphogluconate

    AU - Cameron, Scott

    AU - Martini, Viviane P.

    AU - Iulek, Jorge

    AU - Hunter, William N.

    PY - 2009/5

    Y1 - 2009/5

    N2 - Two crystal structures of recombinant Geobacillus stearothermophilus 6-phosphogluconate dehydrogenase (Gs6PDH) in complex with the substrate 6-phosphogluconate have been determined at medium resolution. Gs6PDH shares significant sequence identity and structural similarity with the enzymes from Lactococcus lactis, sheep liver and the protozoan parasite Trypanosoma brucei, for which a range of structures have previously been reported. Comparisons indicate that amino-acid sequence conservation is more pronounced in the two domains that contribute to the architecture of the active site, namely the N-terminal and C-terminal domains, compared with the central domain, which is primarily involved in the subunit-subunit associations required to form a stable dimer. The active-site residues are highly conserved, as are the interactions with the 6-phosphogluconate. There is interest in 6PDH as a potential drug target for the protozoan parasite T. brucei, the pathogen responsible for African sleeping sickness. The recombinant T. brucei enzyme has proven to be recalcitrant to enzyme-ligand studies and a surrogate protein might offer new opportunities to investigate and characterize 6PDH inhibitors. The high degree of structural similarity, efficient level of expression and straightforward crystallization conditions mean that Gs6PDH may prove to be an appropriate model system for structure-based inhibitor design targeting the enzyme from Trypanosoma species.

    AB - Two crystal structures of recombinant Geobacillus stearothermophilus 6-phosphogluconate dehydrogenase (Gs6PDH) in complex with the substrate 6-phosphogluconate have been determined at medium resolution. Gs6PDH shares significant sequence identity and structural similarity with the enzymes from Lactococcus lactis, sheep liver and the protozoan parasite Trypanosoma brucei, for which a range of structures have previously been reported. Comparisons indicate that amino-acid sequence conservation is more pronounced in the two domains that contribute to the architecture of the active site, namely the N-terminal and C-terminal domains, compared with the central domain, which is primarily involved in the subunit-subunit associations required to form a stable dimer. The active-site residues are highly conserved, as are the interactions with the 6-phosphogluconate. There is interest in 6PDH as a potential drug target for the protozoan parasite T. brucei, the pathogen responsible for African sleeping sickness. The recombinant T. brucei enzyme has proven to be recalcitrant to enzyme-ligand studies and a surrogate protein might offer new opportunities to investigate and characterize 6PDH inhibitors. The high degree of structural similarity, efficient level of expression and straightforward crystallization conditions mean that Gs6PDH may prove to be an appropriate model system for structure-based inhibitor design targeting the enzyme from Trypanosoma species.

    KW - PENTOSE-PHOSPHATE PATHWAY

    KW - TRYPANOSOMA-BRUCEI

    KW - SUBSTRATE-BINDING

    KW - ENZYME

    KW - SPECIFICITY

    KW - DIFFRACTION

    KW - MECHANISM

    KW - COENZYME

    KW - QUALITY

    KW - ANALOGS

    U2 - 10.1107/S1744309109012767

    DO - 10.1107/S1744309109012767

    M3 - Article

    VL - 65

    SP - 450

    EP - 454

    JO - Acta Crystallographica F-Structural Biology and Crystallization Communications

    JF - Acta Crystallographica F-Structural Biology and Crystallization Communications

    SN - 1744-3091

    ER -