Discovery of an Allosteric Inhibitor Binding Site in 3-Oxo-acyl-ACP Reductase from Pseudomonas aeruginosa

Cyprian D. Cukier, Anthony G. Hope, Ayssar A. Elamin, Lucile Moynie, Robert Schnell, Susanne Schach, Holger Kneuper, Mahavir Singh, James H. Naismith, Ylva Lindqvist, David W. Gray*, Gunter Schneider

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

22 Citations (Scopus)

Abstract

3-Oxo-acyl-acyl carrier protein (ACP) reductase (FabG) plays a key role in the bacterial fatty acid synthesis II system in pathogenic microorganisms, which has been recognized as a potential drug target. FabG catalyzes reduction of a 3-oxo-acyl-ACP intermediate during the elongation cycle of fatty acid biosynthesis. Here, we report gene deletion experiments that support the essentiality of this gene in P. aeruginosa and the identification of a number of small molecule FabG inhibitors with IC50 values in the nanomolar to low micromolar range and good physicochemical properties. Structural characterization of 16 FabG-inhibitor complexes by X-ray crystallography revealed that the compounds bind at a novel allosteric site located at the FabG subunit-subunit interface. Inhibitor binding relies primarily on hydrophobic interactions, but specific hydrogen bonds are also observed. Importantly, the binding cavity is formed upon complex formation and therefore would not be recognized by virtual screening approaches. The structure analysis further reveals that the inhibitors act by inducing conformational changes that propagate to the active site, resulting in a displacement of the catalytic triad and the inability to bind NADPH.

Original languageEnglish
Pages (from-to)2518-2527
Number of pages10
JournalACS Chemical Biology
Volume8
Issue number11
DOIs
Publication statusPublished - Nov 2013

Keywords

  • FATTY-ACID BIOSYNTHESIS
  • ACYL CARRIER PROTEIN
  • ANTIBACTERIAL DRUG DISCOVERY
  • CRYSTAL-STRUCTURE
  • MYCOBACTERIUM-TUBERCULOSIS
  • ESCHERICHIA-COLI
  • PLASMODIUM-FALCIPARUM
  • FABG
  • TARGETS
  • RESISTANCE

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