ArticleACS chemical biology2013
Discovery of an allosteric inhibitor binding site in 3-Oxo-acyl-ACP reductase from Pseudomonas aeruginosa.
Article in ACS chemical biology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 37 citations in OpenAlex.
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- Structure features ofFrontiers in molecular biosciences · 2024Article
- Deciphering the structure of a multi-drug resistant Acinetobacter baumannii short-chain dehydrogenase reductase.PloS one · 2024Article
- Lipid-Centric Approaches in Combating Infectious Diseases: Antibacterials, Antifungals and Antivirals with Lipid-Associated Mechanisms of Action.Antibiotics (Basel, Switzerland) · 2023Review
- Structure and dynamics of pteridine reductase 1: the key phenomena relevant to enzyme function and drug design.European biophysics journal : EBJ · 2023Review
- Design and Synthesis of Covalent Inhibitors of FabA.ACS omega · 2023Article
- A Review of Fatty Acid Biosynthesis Enzyme Inhibitors as Promising Antimicrobial Drugs.Pharmaceuticals (Basel, Switzerland) · 2023Review
- Using Structure-guided Fragment-Based Drug Discovery to TargetFrontiers in molecular biosciences · 2022Review
- Structural comparison of Acinetobacter baumannii β-ketoacyl-acyl carrier protein reductases in fatty acid and aryl polyene biosynthesis.Scientific reports · 2021Article
- An integrated genomic regulatory network of virulence-related transcriptional factors in Pseudomonas aeruginosa.Nature communications · 2019Article
- Validation of the anti-infective potential of a polyherbal 'Panchvalkal' preparation, and elucidation of the molecular basis underlining its efficacy against Pseudomonas aeruginosa.BMC complementary and alternative medicine · 2019Article
- Tachyplesin Causes Membrane Instability That Kills Multidrug-Resistant Bacteria by Inhibiting the 3-Ketoacyl Carrier Protein Reductase FabG.Frontiers in microbiology · 2018Article
- Advance in Research onFrontiers in microbiology · 2018Article
- Stabilization of Multimeric Proteins via Intersubunit Cyclization.Applied and environmental microbiology · 2017Article
- Comparison of two bioinformatics tools used to characterize the microbial diversity and predictive functional attributes of microbial mats from Lake Obersee, Antarctica.Journal of microbiological methods · 2017Article
- Dissecting the Structural Elements for the Activation of β-Ketoacyl-(Acyl Carrier Protein) Reductase from Vibrio cholerae.Journal of bacteriology · 2016Article
- A Substrate Mimic Allows High-Throughput Assay of the FabA Protein and Consequently the Identification of a Novel Inhibitor of Pseudomonas aeruginosa FabA.Journal of molecular biology · 2016Article
- Cloning, expression, purification, crystallization and preliminary X-ray diffraction analysis of AerF from Microcystis aeruginosa, a putative reductase participating in aeruginosin biosynthesis.Acta crystallographica. Section F, Structural biology communications · 2015Article
- Using modern tools to probe the structure-function relationship of fatty acid synthases.Chembiochem : a European journal of chemical biology · 2015Review
- Structural Characterisation of FabG from Yersinia pestis, a Key Component of Bacterial Fatty Acid Synthesis.PloS one · 2015Article
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Authors and funding
12 authors at 2 institutions in 2 countries.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.