3QLR

Candida albicans dihydrofolate reductase complexed with NADPH and 6-methyl-5-[(3R)-3-(3,4,5-trimethoxyphenyl)pent-1-yn-1-yl]pyrimidine-2,4-diamine (UCP112A)

Summary for 3QLR

• Entry DOI: 10.2210/pdb3qlr/pdb
• Related: 1AI9 1AOE 1IA1 1IA2 1IA3 1IA4 1M78 1M79 1M7A
• Descriptor: Putative uncharacterized protein CaJ7.0360, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, 6-methyl-5-[(3R)-3-(3,4,5-trimethoxyphenyl)pent-1-yn-1-yl]pyrimidine-2,4-diamine, ... (6 entities in total)
• Functional Keywords: antifungal agents, candida albicans, drug design, enzyme inhibitors, fungal proteins, models, molecular structure, structure-activity relationship, tetrahydrofolate dehydrogenase, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• Biological source: Candida albicans (yeast)
• Total number of polymer chains: 2
• Total formula weight: 46927.06

Authors

Paulsen, J.L.,Bendel, S.D.,Anderson, A.C. (deposition date: 2011-02-03, release date: 2011-07-20, Last modification date: 2023-09-13)

Primary citation

Paulsen, J.L.,Bendel, S.D.,Anderson, A.C.
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.
Chem.Biol.Drug Des., 78:505-512, 2011

PubMed Abstract: 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 C. 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 and 3 Å 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.

PubMed: 21726415
DOI: 10.1111/j.1747-0285.2011.01169.x

Experimental method

X-RAY DIFFRACTION (2.149 Å)