4bnj

Crystal structure of S. aureus FabI in complex with NADP and 5-methyl- 2-phenoxyphenol

spinqualitylabelsall models 4bnj, resolution 2.40Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4bnj is a 8 chain structure with sequence from Staphylococcus aureus subsp. aureus N315. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.4Å Ligands: GLU, MJ5, NAP Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function A0A0H3JLH9_STAAN Publication Abstract from PubMed Drug-target kinetics has recently emerged as an especially important facet of the drug discovery process. In particular, prolonged drug-target residence times may confer enhanced efficacy and selectivity in the open in vivo system. However, the lack of accurate kinetic and structural data for series of congeneric compounds hinders the rational design of inhibitors with decreased off-rates. Therefore, we chose the Staphylococcus aureus enoyl-ACP reductase (saFabI) - an important target for the development of new anti-staphylococcal drugs - as a model system to rationalize and optimize the drug-target residence time on a structural basis. Using our new, efficient and widely applicable mechanistically informed kinetic approach, we obtained a full characterization of saFabI inhibition by a series of 20 diphenyl ethers complemented by a collection of 9 saFabI-inhibitor crystal structures. We identified a strong correlation between the affinities of the investigated saFabI diphenyl ether inhibitors and their corresponding residence times, which can be rationalized on a structural basis. Due to its favorable interactions with the enzyme, the residence time of our most potent compound exceeds 10 hours. In addition, we found that affinity and residence time in this system can be significantly enhanced by modifications predictable by a careful consideration of catalysis. Our study provides a blueprint for investigating and prolonging drug-target kinetics and may aid in the rational design of long-residence-time inhibitors targeting the essential saFabI enzyme. Rational optimization of drug-target residence time: Insights from inhibitor binding to the S. aureus FabI enzyme-product complex.,Chang A, Schiebel J, Yu W, Bommineni GR, Pan P, Baxter MV, Khanna A, Sotriffer CA, Kisker CF, Tonge PJ Biochemistry. 2013 May 22. PMID:23697754 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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