4FGH

S. aureus dihydrofolate reductase co-crystallized with ethyl-DAP isobutenyl-dihydrophthalazine inhibitor

4FGH の概要

• エントリーDOI: 10.2210/pdb4fgh/pdb
• 関連するPDBエントリー: 3M08 4FGG
• 分子名称: Dihydrofolate reductase, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, (2E)-3-{5-[(2,4-diamino-6-ethylpyrimidin-5-yl)methyl]-2,3-dimethoxyphenyl}-1-[(1S)-1-(2-methylprop-1-en-1-yl)phthalazin-2(1H)-yl]prop-2-en-1-one, ... (5 entities in total)
• 機能のキーワード: oxidoreductase-inhibitor complex, oxidoreductase/inhibitor
• 由来する生物種: Staphylococcus aureus
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 20104.66

構造登録者

Bourne, C.R.,Barrow, W.W. (登録日: 2012-06-04, 公開日: 2013-01-09, 最終更新日: 2024-02-28)

主引用文献

Nammalwar, B.,Bourne, C.R.,Bunce, R.A.,Wakeham, N.,Bourne, P.C.,Ramnarayan, K.,Mylvaganam, S.,Berlin, K.D.,Barrow, E.W.,Barrow, W.W.
Inhibition of Bacterial Dihydrofolate Reductase by 6-Alkyl-2,4-diaminopyrimidines.
Chemmedchem, 7:1974-1982, 2012

PubMed Abstract: (±)-6-Alkyl-2,4-diaminopyrimidine-based inhibitors of bacterial dihydrofolate reductase (DHFR) have been prepared and evaluated for biological potency against Bacillus anthracis and Staphylococcus aureus. Biological studies revealed attenuated activity relative to earlier structures lacking substitution at C6 of the diaminopyrimidine moiety, though minimum inhibitory concentration (MIC) values are in the 0.125-8 μg mL(-1) range for both organisms. This effect was rationalized from three- dimensional X-ray structure studies that indicate the presence of a side pocket containing two water molecules adjacent to the main binding pocket. Because of the hydrophobic nature of the substitutions at C6, the main interactions are with protein residues Leu 20 and Leu 28. These interactions lead to a minor conformational change in the protein, which opens the pocket containing these water molecules such that it becomes continuous with the main binding pocket. These water molecules are reported to play a critical role in the catalytic reaction, highlighting a new area for inhibitor expansion within the limited architectural variation at the catalytic site of bacterial DHFR.

PubMed: 22930550
DOI: 10.1002/cmdc.201200291

実験手法

X-RAY DIFFRACTION (2.5 Å)