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PDBsum entry 4jb6
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References listed in PDB file
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Key reference
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Title
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Structures of pseudomonas aeruginosa β-Ketoacyl-(Acyl-Carrier-Protein) synthase ii (fabf) and a c164q mutant provide templates for antibacterial drug discovery and identify a buried potassium ion and a ligand-Binding site that is an artefact of the crystal form.
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Authors
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B.Baum,
L.S.Lecker,
M.Zoltner,
E.Jaenicke,
R.Schnell,
W.N.Hunter,
R.Brenk.
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Ref.
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Acta Crystallogr F Struct Biol Commun, 2015,
71,
1020-1026.
[DOI no: ]
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PubMed id
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Abstract
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Bacterial infections remain a serious health concern, in particular causing
life-threatening infections of hospitalized and immunocompromised patients. The
situation is exacerbated by the rise in antibacterial drug resistance, and new
treatments are urgently sought. In this endeavour, accurate structures of
molecular targets can support early-stage drug discovery. Here, crystal
structures, in three distinct forms, of recombinant Pseudomonas aeruginosa
β-ketoacyl-(acyl-carrier-protein) synthase II (FabF) are presented. This
enzyme, which is involved in fatty-acid biosynthesis, has been validated by
genetic and chemical means as an antibiotic target in Gram-positive bacteria and
represents a potential target in Gram-negative bacteria. The structures of apo
FabF, of a C164Q mutant in which the binding site is altered to resemble the
substrate-bound state and of a complex with 3-(benzoylamino)-2-hydroxybenzoic
acid are reported. This compound mimics aspects of a known natural product
inhibitor, platensimycin, and surprisingly was observed binding outside the
active site, interacting with a symmetry-related molecule. An unusual feature is
a completely buried potassium-binding site that was identified in all three
structures. Comparisons suggest that this may represent a conserved structural
feature of FabF relevant to fold stability. The new structures provide templates
for structure-based ligand design and, together with the protocols and reagents,
may underpin a target-based drug-discovery project for urgently needed
antibacterials.
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