6VCJ

Crystal structure of hsDHFR in complex with NADP+, DAP, and R-naproxen

6VCJ の概要

• エントリーDOI: 10.2210/pdb6vcj/pdb
• 分子名称: Dihydrofolate reductase, PYRIMIDINE-2,4-DIAMINE, (2R)-2-(6-methoxynaphthalen-2-yl)propanoic acid, ... (6 entities in total)
• 機能のキーワード: nadp+, 2, 4-diaminopyridine, r-naproxen, inhibitor, complex, oxidoreductase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 92251.81

構造登録者

Pedersen, L.C.,London, R.E.,Gabel, S.A.,Krahn, J.M.,DeRose, E.F. (登録日: 2019-12-21, 公開日: 2020-10-28, 最終更新日: 2023-10-11)

主引用文献

Duff Jr., M.R.,Gabel, S.A.,Pedersen, L.C.,DeRose, E.F.,Krahn, J.M.,Howell, E.E.,London, R.E.
The Structural Basis for Nonsteroidal Anti-Inflammatory Drug Inhibition of Human Dihydrofolate Reductase.
J.Med.Chem., 63:8314-8324, 2020

PubMed Abstract: Although nonsteroidal anti-inflammatory drugs (NSAIDs) target primarily cyclooxygenase enzymes, a subset of NSAIDs containing carboxylate groups also has been reported to competitively inhibit dihydrofolate reductase (DHFR). In this study, we have characterized NSAID interactions with human DHFR based on kinetic, NMR, and X-ray crystallographic methods. The NSAIDs target a region of the folate binding site that interacts with the -aminobenzoyl-l-glutamate (pABG) moiety of folate and inhibit cooperatively with ligands that target the adjacent pteridine-recognition subsite. NSAIDs containing benzoate or salicylate groups were identified as having the highest potency. Among those tested, diflunisal, a salicylate derivative not previously identified to have anti-folate activity, was found to have a of 34 μM, well below peak plasma diflunisal levels reached at typical dosage levels. The potential of these drugs to interfere with the inflammatory process by multiple pathways introduces the possibility of further optimization to design dual-targeted analogs.

PubMed: 32658475
DOI: 10.1021/acs.jmedchem.0c00546

実験手法

X-RAY DIFFRACTION (2.34 Å)