1S2C

Crystal structures of prostaglandin D2 11-ketoreductase in complex with the non-steroidal anti-inflammatory drugs flufenamic acid and indomethacin

1S2C の概要

• エントリーDOI: 10.2210/pdb1s2c/pdb
• 関連するPDBエントリー: 1S1P 1S1R 1S2A
• 分子名称: Aldo-keto reductase family 1 member C3, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, 2-[[3-(TRIFLUOROMETHYL)PHENYL]AMINO] BENZOIC ACID, ... (5 entities in total)
• 機能のキーワード: tim-barrel, oxidoreductase
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm: P42330
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 39351.35

構造登録者

Lovering, A.L.,Ride, J.P.,Bunce, C.M.,Desmond, J.C.,Cummings, S.M.,White, S.A. (登録日: 2004-01-08, 公開日: 2004-03-23, 最終更新日: 2023-10-25)

主引用文献

Lovering, A.L.,Ride, J.P.,Bunce, C.M.,Desmond, J.C.,Cummings, S.M.,White, S.A.
Crystal structures of prostaglandin D(2) 11-ketoreductase (AKR1C3) in complex with the nonsteroidal anti-inflammatory drugs flufenamic acid and indomethacin.
Cancer Res., 64:1802-1810, 2004

PubMed Abstract: It is becoming increasingly well established that nonsteroidal anti-inflammatory drugs (NSAID) protect against tumors of the gastrointestinal tract and that they may also protect against a variety of other tumors. These activities have been widely attributed to the inhibition of cylooxygenases (COX) and, in particular, COX-2. However, several observations have indicated that other targets may be involved. Besides targeting COX, certain NSAID also inhibit enzymes belonging to the aldo-keto reductase (AKR) family, including AKR1C3. We have demonstrated previously that overexpression of AKR1C3 acts to suppress cell differentiation and promote proliferation in myeloid cells. However, this enzyme has a broad tissue distribution and therefore represents a novel candidate for the target of the COX-independent antineoplastic actions of NSAID. Here we report on the X-ray crystal structures of AKR1C3 complexed with the NSAID indomethacin (1.8 A resolution) or flufenamic acid (1.7 A resolution). One molecule of indomethacin is bound in the active site, whereas flufenamic acid binds to both the active site and the beta-hairpin loop, at the opposite end of the central beta-barrel. Two other crystal structures (1.20 and 2.1 A resolution) show acetate bound in the active site occupying the proposed oxyanion hole. The data underline AKR1C3 as a COX-independent target for NSAID and will provide a structural basis for the future development of new cancer therapies with reduced COX-dependent side effects.

PubMed: 14996743
DOI: 10.1158/0008-5472.CAN-03-2847

実験手法

X-RAY DIFFRACTION (1.8 Å)