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[[Image:1s1p.gif|left|200px]]


{{Structure
==Crystal structures of prostaglandin D2 11-ketoreductase (AKR1C3) in complex with the non-steroidal anti-inflammatory drugs flufenamic acid and indomethacin==
|PDB= 1s1p |SIZE=350|CAPTION= <scene name='initialview01'>1s1p</scene>, resolution 1.20&Aring;
<StructureSection load='1s1p' size='340' side='right'caption='[[1s1p]], [[Resolution|resolution]] 1.20&Aring;' scene=''>
|SITE=  
== Structural highlights ==
|LIGAND= <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>
<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>
|ACTIVITY=  
</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>
|GENE=  
<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>
|DOMAIN=
<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>
|RELATEDENTRY=[[1s1r|1S1R]], [[1s2a|1S2A]], [[1s2c|1S2C]]
</table>
|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1s1p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1s1p OCA], [http://www.ebi.ac.uk/pdbsum/1s1p PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1s1p RCSB]</span>
== Function ==
}}
[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.
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/s1/1s1p_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</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].
<div style="clear:both"></div>


'''Crystal structures of prostaglandin D2 11-ketoreductase (AKR1C3) in complex with the non-steroidal anti-inflammatory drugs flufenamic acid and indomethacin'''
==See Also==
 
*[[Prostaglandin F synthase 3D structures|Prostaglandin F synthase 3D structures]]
 
__TOC__
==Overview==
</StructureSection>
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.
 
==About this Structure==
1S1P is a [[Single protein]] structure of sequence from [http://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].
 
==Reference==
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://www.ncbi.nlm.nih.gov/pubmed/14996743 14996743]
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Single protein]]
[[Category: Large Structures]]
[[Category: Bunce, C M.]]
[[Category: Bunce CM]]
[[Category: Cummings, S M.]]
[[Category: Cummings SM]]
[[Category: Desmond, J C.]]
[[Category: Desmond JC]]
[[Category: Lovering, A L.]]
[[Category: Lovering AL]]
[[Category: Ride, J P.]]
[[Category: Ride JP]]
[[Category: White, S A.]]
[[Category: White SA]]
[[Category: tim-barrel]]
 
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