3QLX

Candida glabrata 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)

3QLX の概要

• エントリーDOI: 10.2210/pdb3qlx/pdb
• 関連するPDBエントリー: 3CSE 3EEJ 3EEK 3EEL 3EEM
• 分子名称: Dihydrofolate reductase, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, 6-methyl-5-[(3R)-3-(3,4,5-trimethoxyphenyl)pent-1-yn-1-yl]pyrimidine-2,4-diamine, ... (4 entities in total)
• 機能のキーワード: antifungal agents, candida glabrata, drug design, enzyme inhibitors, fungal proteins, models, molecular structure, structure-activity relationship, tetrahydrofolate dehydrogenase, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• 由来する生物種: Candida glabrata (yeast)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 55058.35

構造登録者

Paulsen, J.L.,Bendel, S.D.,Anderson, A.C. (登録日: 2011-02-03, 公開日: 2011-07-20, 最終更新日: 2023-09-13)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.239 Å)