Crystal structures of prostaglandin D(2) 11-ketoreductase (AKR1C3) in complex with the nonsteroidal anti-inflammatory drugs flufenamic acid and indomethacin

Cancer Res. 2004 Mar 1;64(5):1802-10. doi: 10.1158/0008-5472.can-03-2847.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Anti-Inflammatory Agents, Non-Steroidal / metabolism*
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology
  • Binding Sites
  • Crystallization
  • Cyclooxygenase Inhibitors / pharmacology
  • Flufenamic Acid / metabolism*
  • Hydroxyprostaglandin Dehydrogenases / antagonists & inhibitors
  • Hydroxyprostaglandin Dehydrogenases / chemistry*
  • Hydroxyprostaglandin Dehydrogenases / metabolism
  • Indomethacin / metabolism*
  • Molecular Sequence Data
  • Protein Structure, Secondary
  • Recombinant Proteins / chemistry


  • Anti-Inflammatory Agents, Non-Steroidal
  • Cyclooxygenase Inhibitors
  • Recombinant Proteins
  • Flufenamic Acid
  • Hydroxyprostaglandin Dehydrogenases
  • prostaglandin-F synthase
  • Indomethacin