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PDBsum entry 1s2a
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Oxidoreductase
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PDB id
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1s2a
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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Crystal structures of prostaglandin d(2) 11-Ketoreductase (akr1c3) in complex with the nonsteroidal anti-Inflammatory drugs flufenamic acid and indomethacin.
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Authors
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A.L.Lovering,
J.P.Ride,
C.M.Bunce,
J.C.Desmond,
S.M.Cummings,
S.A.White.
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Ref.
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Cancer Res, 2004,
64,
1802-1810.
[DOI no: ]
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PubMed id
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Abstract
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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.
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