4bnt Citations

Discovery of an allosteric inhibitor binding site in 3-oxo-acyl-ACP reductase from Pseudomonas aeruginosa.


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 sixteen 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.

Reviews citing this publication (2)

  1. Fatty acid biosynthesis revisited: structure elucidation and metabolic engineering. Beld J, Lee DJ, Burkart MD. Mol Biosyst 11 38-59 (2015)
  2. Using modern tools to probe the structure-function relationship of fatty acid synthases. Finzel K, Lee DJ, Burkart MD. Chembiochem 16 528-547 (2015)

Articles citing this publication (4)

  1. Structural Characterisation of FabG from Yersinia pestis, a Key Component of Bacterial Fatty Acid Synthesis. Nanson JD, Forwood JK. PLoS ONE 10 e0141543 (2015)
  2. Dissecting the Structural Elements for the Activation of β-Ketoacyl-(Acyl Carrier Protein) Reductase from Vibrio cholerae. Hou J, Zheng H, Chruszcz M, Zimmerman MD, Shumilin IA, Osinski T, Demas M, Grimshaw S, Minor W. J. Bacteriol. 198 463-476 (2015)
  3. A Substrate Mimic Allows High-Throughput Assay of the FabA Protein and Consequently the Identification of a Novel Inhibitor of Pseudomonas aeruginosa FabA. Moynié L, Hope AG, Finzel K, Schmidberger J, Leckie SM, Schneider G, Burkart MD, Smith AD, Gray DW, Naismith JH. J. Mol. Biol. 428 108-120 (2016)
  4. Comparison of two bioinformatics tools used to characterize the microbial diversity and predictive functional attributes of microbial mats from Lake Obersee, Antarctica. Koo H, Hakim JA, Morrow CD, Eipers PG, Davila A, Andersen DT, Bej AK. J. Microbiol. Methods 140 15-22 (2017)