3qlw | pdb_00003qlw

Candida albicans dihydrofolate reductase complexed with NADPH and 5-[3-(2,5-dimethoxyphenyl)prop-1-yn-1-yl]-6-ethylpyrimidine-2,4-diamine (UCP120B)

spinqualitylabelsall models 3qlw, resolution 2.50Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3qlw is a 2 chain structure with sequence from Candida albicans. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: N22, NDP Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function DYR_CANAX Key enzyme in folate metabolism. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis. Publication Abstract from PubMed Candida albicans and Candida glabrata cause fungal bloodstream infections that are associated with significant mortality. As part of an effort to develop potent and selective antifolates that target dihydrofolate reductase (DHFR) from Candida species, we report three ternary crystal structures of Candida albicans DHFR (CaDHFR) bound to novel propargyl-linked analogs. Consistent with earlier modeling results, these structures show that hydrophobic pockets in the binding site may be exploited to increase ligand potency. The crystal structures also confirm that loop residues Thr 58- Phe 66, which flank the active site and influence ligand potency and selectivity, adopt multiple conformations. To aid the development of a dual Candida spp. inhibitor, three new crystal structures of C. glabrata DHFR (CgDHFR) bound to similar ligands as those bound in the ternary structures of CaDHFR are also reported here. Loop residues 58-66 in CgDHFR and human DHFR are 1 A and 3 A closer to the folate binding site, respectively, than loop residues in CaDHFR, suggesting that a properly size ligand could be a potent and selective dual inhibitor of CaDHFR and CgDHFR. Crystal structures of Candida albicans dihydrofolate reductase bound to propargyl-linked antifolates reveal the flexibility of active site loop residues critical for ligand potency and selectivity.,Paulsen JL, Bendel SD, Anderson AC Chem Biol Drug Des. 2011 Jul 5. doi: 10.1111/j.1747-0285.2011.01169.x. PMID:21726415 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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