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| {{STRUCTURE_1s1r| PDB=1s1r | SCENE= }} | | {{STRUCTURE_1s1r| PDB=1s1r | SCENE= }} |
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| '''Crystal structures of prostaglandin D2 11-ketoreductase (AKR1C3) in complex with the non-steroidal anti-inflammatory drugs flufenamic acid and indomethacin'''
| | ===Crystal structures of prostaglandin D2 11-ketoreductase (AKR1C3) in complex with the non-steroidal anti-inflammatory drugs flufenamic acid and indomethacin=== |
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| ==Overview==
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| 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.
| | The line below this paragraph, {{ABSTRACT_PUBMED_14996743}}, adds the Publication Abstract to the page |
| | (as it appears on PubMed at http://www.pubmed.gov), where 14996743 is the PubMed ID number. |
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| | {{ABSTRACT_PUBMED_14996743}} |
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| ==About this Structure== | | ==About this Structure== |
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| [[Category: White, S A.]] | | [[Category: White, S A.]] |
| [[Category: Tim-barrel]] | | [[Category: Tim-barrel]] |
| ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 08:11:25 2008'' | | |
| | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Jul 27 14:31:19 2008'' |