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The AEROPATH project targeting Pseudomonas aeruginosa: crystallographic studies for assessment of potential targets in early-stage drug discovery.

Moynie L, Schnell R, McMahon SA, Sandalova T, Boulkerou WA, Schmidberger JW, Alphey M, Cukier C, Duthie F, Kopec J, Liu H, Jacewicz A, Hunter WN, Naismith JH, Schneider G - Acta Crystallogr. Sect. F Struct. Biol. Cryst. Commun. (2012)

Bottom Line: A major concern is Gram-negative bacteria, for which the discovery of new antimicrobial drugs has been particularly scarce.The crystal structures of eight of these targets, ranging from hypothetical unknown proteins to metabolic enzymes from different functional classes (PA1645, PA1648, PA2169, PA3770, PA4098, PA4485, PA4992 and PA5259), are reported here.The structural information is expected to provide a firm basis for the improvement of hit compounds identified from fragment-based and high-throughput screening campaigns.

View Article: PubMed Central - HTML - PubMed

Affiliation: Biomedical Sciences Research Complex, University of St Andrews, St Andrews KY16 9ST, Scotland.

ABSTRACT
Bacterial infections are increasingly difficult to treat owing to the spread of antibiotic resistance. A major concern is Gram-negative bacteria, for which the discovery of new antimicrobial drugs has been particularly scarce. In an effort to accelerate early steps in drug discovery, the EU-funded AEROPATH project aims to identify novel targets in the opportunistic pathogen Pseudomonas aeruginosa by applying a multidisciplinary approach encompassing target validation, structural characterization, assay development and hit identification from small-molecule libraries. Here, the strategies used for target selection are described and progress in protein production and structure analysis is reported. Of the 102 selected targets, 84 could be produced in soluble form and the de novo structures of 39 proteins have been determined. The crystal structures of eight of these targets, ranging from hypothetical unknown proteins to metabolic enzymes from different functional classes (PA1645, PA1648, PA2169, PA3770, PA4098, PA4485, PA4992 and PA5259), are reported here. The structural information is expected to provide a firm basis for the improvement of hit compounds identified from fragment-based and high-throughput screening campaigns.

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Schematic view of the structure of the uncharacterized protein PA4485. The conserved Asp70 is represented as a stick model.
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fig4: Schematic view of the structure of the uncharacterized protein PA4485. The conserved Asp70 is represented as a stick model.

Mentions: PA4485 is a single-domain protein with overall dimensions of 25 × 23 Å. The core of the protein (residues 1–­9 and 26–94) adopts a six-stranded β-barrel fold (Fig. 4 ▶ and Supplementary Fig. 1d). The barrel is sealed off at one end by a seven-residue α-helix positioned between strands β7 and β8. In addition, there is a small extension protruding from the bulk of the protein (residues 10–25). After strand β1 of the barrel fold, this insert folds into a short 310-helix that turns through almost a right angle such that the remaining two short β-strands pack against the core of the protein (Fig. 4 ▶).


The AEROPATH project targeting Pseudomonas aeruginosa: crystallographic studies for assessment of potential targets in early-stage drug discovery.

Moynie L, Schnell R, McMahon SA, Sandalova T, Boulkerou WA, Schmidberger JW, Alphey M, Cukier C, Duthie F, Kopec J, Liu H, Jacewicz A, Hunter WN, Naismith JH, Schneider G - Acta Crystallogr. Sect. F Struct. Biol. Cryst. Commun. (2012)

Schematic view of the structure of the uncharacterized protein PA4485. The conserved Asp70 is represented as a stick model.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3539698&req=5

fig4: Schematic view of the structure of the uncharacterized protein PA4485. The conserved Asp70 is represented as a stick model.
Mentions: PA4485 is a single-domain protein with overall dimensions of 25 × 23 Å. The core of the protein (residues 1–­9 and 26–94) adopts a six-stranded β-barrel fold (Fig. 4 ▶ and Supplementary Fig. 1d). The barrel is sealed off at one end by a seven-residue α-helix positioned between strands β7 and β8. In addition, there is a small extension protruding from the bulk of the protein (residues 10–25). After strand β1 of the barrel fold, this insert folds into a short 310-helix that turns through almost a right angle such that the remaining two short β-strands pack against the core of the protein (Fig. 4 ▶).

Bottom Line: A major concern is Gram-negative bacteria, for which the discovery of new antimicrobial drugs has been particularly scarce.The crystal structures of eight of these targets, ranging from hypothetical unknown proteins to metabolic enzymes from different functional classes (PA1645, PA1648, PA2169, PA3770, PA4098, PA4485, PA4992 and PA5259), are reported here.The structural information is expected to provide a firm basis for the improvement of hit compounds identified from fragment-based and high-throughput screening campaigns.

View Article: PubMed Central - HTML - PubMed

Affiliation: Biomedical Sciences Research Complex, University of St Andrews, St Andrews KY16 9ST, Scotland.

ABSTRACT
Bacterial infections are increasingly difficult to treat owing to the spread of antibiotic resistance. A major concern is Gram-negative bacteria, for which the discovery of new antimicrobial drugs has been particularly scarce. In an effort to accelerate early steps in drug discovery, the EU-funded AEROPATH project aims to identify novel targets in the opportunistic pathogen Pseudomonas aeruginosa by applying a multidisciplinary approach encompassing target validation, structural characterization, assay development and hit identification from small-molecule libraries. Here, the strategies used for target selection are described and progress in protein production and structure analysis is reported. Of the 102 selected targets, 84 could be produced in soluble form and the de novo structures of 39 proteins have been determined. The crystal structures of eight of these targets, ranging from hypothetical unknown proteins to metabolic enzymes from different functional classes (PA1645, PA1648, PA2169, PA3770, PA4098, PA4485, PA4992 and PA5259), are reported here. The structural information is expected to provide a firm basis for the improvement of hit compounds identified from fragment-based and high-throughput screening campaigns.

Show MeSH
Related in: MedlinePlus