5ecc | pdb_00005ecc

Klebsiella pneumoniae DfrA1 complexed with NADPH and 6-ethyl-5-(3-(2-methoxy-5-(pyridin-4-yl)phenyl)prop-1-yn-1-yl)pyrimidine-2,4-diamine

spinqualitylabelsall models 5ecc, resolution 1.87Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5ecc is a 2 chain structure with sequence from Klebsiella pneumoniae. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.87Å Ligands: 6DR, CA, GOL, NAP Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function A4GRC7_KLEPN Publication Abstract from PubMed Multidrug-resistant Enterobacteriaceae, notably Escherichia coli and Klebsiella pneumoniae, have become major health concerns worldwide. Resistance to effective therapeutics is often carried by class I and II integrons that can confer insensitivity to carbapenems, extended spectrum beta-lactamases, the antifolate trimethoprim, fluoroquinolones, and aminoglycosides. Specifically of interest to the study here, a prevalent gene (dfrA1) coding for an insensitive dihydrofolate reductase (DHFR) confers 190- or 1000-fold resistance to trimethoprim for K. pneumoniae and E. coli, respectively. Attaining inhibition of both the wild-type and resistant forms of the enzyme is critical for new antifolates. For several years, we have been developing the propargyl-linked antifolates (PLAs) as effective inhibitors against trimethoprim-resistant DHFR enzymes. Here, we show that the PLAs are active against both the wild-type and DfrA1 DHFR proteins. We report two high-resolution crystal structures of DfrA1 bound to potent PLAs. The structure-activity relationships and crystal structures will be critical in driving the design of broadly active inhibitors against wild-type and resistant DHFR. Crystal Structures of Trimethoprim-Resistant DfrA1 Rationalize Potent Inhibition by Propargyl-Linked Antifolates.,Lombardo MN, G-Dayanandan N, Wright DL, Anderson AC ACS Infect Dis. 2016 Feb 12;2(2):149-56. doi: 10.1021/acsinfecdis.5b00129. Epub, 2016 Jan 4. PMID:27624966 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Dihydrofolate reductase 3D structures

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