1S1P

Crystal structures of prostaglandin D2 11-ketoreductase (AKR1C3) in complex with the non-steroidal anti-inflammatory drugs flufenamic acid and indomethacin

Summary for 1S1P

• Entry DOI: 10.2210/pdb1s1p/pdb
• Related: 1S1R 1S2A 1S2C
• Descriptor: Aldo-keto reductase family 1 member C3, ACETATE ION, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, ... (5 entities in total)
• Functional Keywords: tim-barrel, oxidoreductase
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P42330
• Total number of polymer chains: 1
• Total formula weight: 38887.98

Authors

Lovering, A.L.,Ride, J.P.,Bunce, C.M.,Desmond, J.C.,Cummings, S.M.,White, S.A. (deposition date: 2004-01-07, release date: 2004-03-23, Last modification date: 2024-03-13)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.2 Å)