6tbc

Crystal structure of S. aureus FabI in complex with NADPH and kalimantacin B

spinqualitylabelsall models 6tbc, resolution 2.55Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6tbc is a 8 chain structure with sequence from "micrococcus_aureus"_(rosenbach_1884)_zopf_1885 "micrococcus aureus" (rosenbach 1884) zopf 1885. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: N5H, NDP Activity: [acyl-carrier-protein_reductase_(NADPH,_Re-specific) Enoyl-[acyl-carrier-protein] reductase (NADPH, Re-specific)], with EC number 1.3.1.39 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed The enoyl-acyl carrier protein reductase enzyme FabI is essential for fatty acid biosynthesis in Staphylococcus aureus and represents a promising target for the development of novel, urgently needed anti-staphylococcal agents. Here, we elucidate the mode of action of the kalimantacin antibiotics, a novel class of FabI inhibitors with clinically-relevant activity against multidrug-resistant S. aureus . By combining X-ray crystallography with molecular dynamics simulations, in vitro kinetic studies and chemical derivatization experiments, we characterize the interaction between the antibiotics and their target, and we demonstrate that the kalimantacins bind in a unique conformation that differs significantly from the binding mode of other known FabI inhibitors. We also investigate mechanisms of acquired resistance in S. aureus and identify key residues in FabI that stabilize the binding of the antibiotics. Our findings provide intriguing insights into the mode of action of a novel class of FabI inhibitors that will inspire future anti-staphylococcal drug development. The kalimantacin polyketide antibiotics inhibit fatty acid biosynthesis in Staphylococcus aureus by targeting the enoyl-acyl carrier protein binding site of FabI.,Fage CD, Lathouwers T, Vanmeert M, Gao LJ, Vrancken K, Lammens EM, Weir A, Degroote R, Cuppens H, Kosol S, Simpson TJ, Crump MP, Willis CL, Herdewijn P, Lescrinier E, Lavigne R, Anne J, Masschelein J Angew Chem Int Ed Engl. 2020 Mar 24. doi: 10.1002/anie.201915407. PMID:32208550 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Enoyl-Acyl-Carrier Protein Reductase 3D structures

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