3fl8

Crystal structure of B. anthracis dihydrofolate reductase (DHFR) with RAB1, a TMP-dihydrophthalazine derivative

spinqualitylabelsall models 3fl8, resolution 2.29Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3fl8 is a 8 chain structure with sequence from Bacillus anthracis. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.2881Å Ligands: CA, RAR Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function Q81R22_BACAN Key enzyme in folate metabolism. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis (By similarity).[PIRNR:PIRNR000194] 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 Bacillus anthracis possesses an innate resistance to the antibiotic trimethoprim due to poor binding to dihydrofolate reductase (DHFR); currently, there are no commercial antibacterials that target this enzyme in B. anthracis. We have previously reported a series of dihydrophthalazine-based trimethoprim derivatives that are inhibitors for this target. In the present work, we have synthesized one compound (RAB1) displaying favorable 50% inhibitory concentration (54 nM) and MIC (< or =12.8 microg/ml) values. RAB1 was cocrystallized with the B. anthracis DHFR in the space group P2(1)2(1)2(1), and X-ray diffraction data were collected to a 2.3-A resolution. Binding of RAB1 causes a conformational change of the side chain of Arg58 and Met37 to accommodate the dihydrophthalazine moiety. Unlike the natural substrate or trimethoprim, the dihydrophthalazine group provides a large hydrophobic anchor that embeds within the DHFR active site and accounts for its selective inhibitory activity against B. anthracis. Crystal structure of Bacillus anthracis dihydrofolate reductase with the dihydrophthalazine-based trimethoprim derivative RAB1 provides a structural explanation of potency and selectivity.,Bourne CR, Bunce RA, Bourne PC, Berlin KD, Barrow EW, Barrow WW Antimicrob Agents Chemother. 2009 Jul;53(7):3065-73. Epub 2009 Apr 13. PMID:19364848 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Dihydrofolate reductase 3D structures

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