3fy8

Crystal Structure of Staph. aureus DHFR complexed with NADPH and AR-101

spinqualitylabelsall models 3fy8, resolution 2.20Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3fy8 is a 1 chain structure with sequence from Staphylococcus aureus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.2Å Ligands: NDP, XCF Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function DYR_STAAU Key enzyme in folate metabolism. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis. Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMed Iclaprim is a novel dihydrofolate reductase (DHFR) inhibitor belonging to the 2,4-diaminopyrimidine class of antibiotics, of which trimethoprim (TMP) is the most well known representative. Iclaprim exhibits potent bactericidal activity against major Gram-positive pathogens, notably methicillin-sensitive Staphylococcus aureus (MSSA) and methicillin-resistant S. aureus (MRSA) phenotypes, including TMP-resistant strains. The inhibition properties of racemic iclaprim and of the two enantiomers, termed AR-101 and AR-102, towards S. aureus wild-type DHFR and TMP-resistant F98Y mutant DHFR were determined and compared. Similar to TMP, AR-101, AR-102 and iclaprim are all competitive inhibitors with respect to the substrate dihydrofolate. Iclaprim, AR-101 and AR-102 demonstrated little or no difference in activity towards these enzymes and were significantly more potent than TMP. The crystal structures of S. aureus DHFR and F98Y mutant DHFR were determined as ternary complexes with NADPH and either AR-101, AR-102 or iclaprim. The binding modes of the inhibitors were analysed and compared. The X-ray crystallographic data explain the binding modes of all molecules well and can be used to rationalize the equipotent affinity of AR-101, AR-102 and iclaprim, which is also reflected in their antibacterial properties. Inhibitory properties and X-ray crystallographic study of the binding of AR-101, AR-102 and iclaprim in ternary complexes with NADPH and dihydrofolate reductase from Staphylococcus aureus.,Oefner C, Parisi S, Schulz H, Lociuro S, Dale GE Acta Crystallogr D Biol Crystallogr. 2009 Aug;65(Pt 8):751-7. Epub 2009, Jul 10. PMID:19622858 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Dihydrofolate reductase 3D structures

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