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1s1p

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(New page: 200px<br /> <applet load="1s1p" size="450" color="white" frame="true" align="right" spinBox="true" caption="1s1p, resolution 1.20&Aring;" /> '''Crystal structures ...)
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[[Image:1s1p.gif|left|200px]]<br />
 
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<applet load="1s1p" size="450" color="white" frame="true" align="right" spinBox="true"
 
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caption="1s1p, resolution 1.20&Aring;" />
 
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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'''<br />
 
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==Overview==
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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==
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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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<StructureSection load='1s1p' size='340' side='right'caption='[[1s1p]], [[Resolution|resolution]] 1.20&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[1s1p]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1S1P OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1S1P FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.2&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=MPD:(4S)-2-METHYL-2,4-PENTANEDIOL'>MPD</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1s1p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1s1p OCA], [https://pdbe.org/1s1p PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1s1p RCSB], [https://www.ebi.ac.uk/pdbsum/1s1p PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1s1p ProSAT]</span></td></tr>
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</table>
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== Function ==
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[https://www.uniprot.org/uniprot/AK1C3_HUMAN AK1C3_HUMAN] Catalyzes the conversion of aldehydes and ketones to alcohols. Catalyzes the reduction of prostaglandin (PG) D2, PGH2 and phenanthrenequinone (PQ) and the oxidation of 9-alpha,11-beta-PGF2 to PGD2. Functions as a bi-directional 3-alpha-, 17-beta- and 20-alpha HSD. Can interconvert active androgens, estrogens and progestins with their cognate inactive metabolites. Preferentially transforms androstenedione (4-dione) to testosterone.
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/s1/1s1p_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1s1p ConSurf].
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<div style="clear:both"></div>
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==About this Structure==
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==See Also==
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1S1P is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with ACT, NAP and MPD as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1S1P OCA].
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*[[Prostaglandin F synthase 3D structures|Prostaglandin F synthase 3D structures]]
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__TOC__
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==Reference==
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</StructureSection>
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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., Lovering AL, Ride JP, Bunce CM, Desmond JC, Cummings SM, White SA, Cancer Res. 2004 Mar 1;64(5):1802-10. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=14996743 14996743]
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[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Single protein]]
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[[Category: Large Structures]]
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[[Category: Bunce, C.M.]]
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[[Category: Bunce CM]]
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[[Category: Cummings, S.M.]]
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[[Category: Cummings SM]]
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[[Category: Desmond, J.C.]]
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[[Category: Desmond JC]]
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[[Category: Lovering, A.L.]]
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[[Category: Lovering AL]]
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[[Category: Ride, J.P.]]
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[[Category: Ride JP]]
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[[Category: White, S.A.]]
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[[Category: White SA]]
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[[Category: ACT]]
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[[Category: MPD]]
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[[Category: NAP]]
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[[Category: tim-barrel]]
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''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 19:09:26 2007''
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Current revision

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

PDB ID 1s1p

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