4cv1

Crystal structure of S. aureus FabI in complex with NADPH and CG400549

spinqualitylabelsall models 4cv1, resolution 1.95Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4cv1 is a 8 chain structure with sequence from Ecobd. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: CL, EDO, NDP, PT6, SO4 Related: 4cuz, 4cv0, 4cv2, 4cv3 Activity: [acyl-carrier-protein_reductase_(NADPH,_B-specific) Enoyl-[acyl-carrier-protein] reductase (NADPH, B-specific)], with EC number 1.3.1.10 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed Determining the molecular basis for target selectivity is of particular importance in drug discovery. The ideal antibiotic should be active against a broad spectrum of pathogenic organisms with a minimal effect on human targets. CG400549 - a Staphylococcus-specific 2-pyridone compound that inhibits the enoyl-ACP reductase (FabI) - has recently been shown to possess human efficacy for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections (www.crystalgenomics.com), which constitute a serious threat to human health. In this study, we solved the structures of three different FabI homologues in complex with several pyridone inhibitors including CG400549. Based on these structures we rationalize the 65-fold reduced affinity of CG400549 towards Escherichia coli vs. S. aureus FabI and implement concepts to improve the spectrum of antibacterial activity. The identification of different conformational states along the reaction coordinate of the enzymatic hydride transfer provides an elegant visual depiction of the relationship between catalysis and inhibition, which facilitates rational inhibitor design. Ultimately, we developed the novel 4-pyridone-based FabI inhibitor PT166 that retained favorable pharmacokinetics and efficacy in a mouse model of S. aureus infection with extended activity against Gram-negative and mycobacterial organisms. Rational Design of Broad-Spectrum Antibacterial Activity based on a Clinically Relevant Enoyl-ACP Reductase Inhibitor.,Schiebel J, Chang A, Shah S, Lu Y, Liu L, Pan P, Hirschbeck MW, Tareilus M, Eltschkner S, Yu W, Cummings JE, Knudson SE, Bommineni GR, Walker SG, Slayden RA, Sotriffer CA, Tonge PJ, Kisker C J Biol Chem. 2014 Apr 16. PMID:24739388 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Enoyl-Acyl-Carrier Protein Reductase

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