Geobacillus stearothermophilus 6-phosphogluconate dehydrogenase complexed with 6-phosphogluconate

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

Research output: Contribution to journalArticle

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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 Section F: Structural Biology and Crystallization Communications
Volume65
Issue number5
DOIs
Publication statusPublished - May 2009
Externally publishedYes

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stearothermophilus
Phosphogluconate Dehydrogenase
Geobacillus stearothermophilus
dehydrogenases
Trypanosoma brucei brucei
enzymes
parasites
Enzymes
inhibitors
Catalytic Domain
Parasites
sicknesses
African Trypanosomiasis
sheep
Trypanosoma
Lactococcus lactis
pathogens
Pathogens
Crystallization
liver

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

In: Acta Crystallographica Section F: Structural Biology and Crystallization Communications, Vol. 65, No. 5, 05.2009, p. 450-454.

Research output: Contribution to journalArticle

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

AU - Cameron, Scott

AU - Martini, Viviane P.

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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.

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