6t77

Crystal structure of Klebsiella pneumoniae FabG(NADPH-dependent) NADP-complex at 1.75 A resolution

spinqualitylabelsall models 6t77, resolution 1.75Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6t77 is a 2 chain structure with sequence from Klebsiella pneumoniae. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.75Å Ligands: NAP Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function W9B6I8_KLEPN Catalyzes the NADPH-dependent reduction of beta-ketoacyl-ACP substrates to beta-hydroxyacyl-ACP products, the first reductive step in the elongation cycle of fatty acid biosynthesis.[ARBA:ARBA00002607][RuleBase:RU366074] Publication Abstract from PubMed The spread of antibiotic resistance within the ESKAPE group of human pathogenic bacteria poses severe challenges in the treatment of infections and maintenance of safe hospital environments. This motivates efforts to validate novel target proteins within these species that could be pursued as potential targets for antibiotic development. Genetic data suggest that the enzyme FabG, which is part of the bacterial fatty acid biosynthetic system FAS-II, is essential in several ESKAPE pathogens. FabG catalyzes the NADPH dependent reduction of 3-keto-acyl-ACP during fatty acid elongation, thus enabling lipid supply for production and maintenance of the cell envelope. Here we report on small-molecule screening on the FabG enzymes from A. baumannii and S. typhimurium to identify a set of microM inhibitors, with the most potent representative (1) demonstrating activity against six FabG-orthologues. A co-crystal structure with FabG from A. baumannii (PDB:6T65) confirms inhibitor binding at an allosteric site located in the subunit interface, as previously demonstrated for other sub-microM inhibitors of FabG from P. aeruginosa. We show that inhibitor binding distorts the oligomerization interface in the FabG tetramer and displaces crucial residues involved in the interaction with the co-substrate NADPH. These observations suggest a conserved allosteric site across the FabG family, which can be potentially targeted for interference with fatty acid biosynthesis in clinically relevant ESKAPE pathogens. A FabG inhibitor targeting an allosteric binding site inhibits several orthologs from Gram-negative ESKAPE pathogens.,Vella P, Rudraraju RS, Lundback T, Axelsson H, Almqvist H, Vallin M, Schneider G, Schnell R Bioorg Med Chem. 2021 Jan 15;30:115898. doi: 10.1016/j.bmc.2020.115898. Epub 2020, Dec 5. PMID:33388594 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Beta-hydroxyacyl-acyl carrier protein dehydratase 3D structures

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