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4fa3

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==Crystal structure of human 17beta-hydroxysteroid dehydrogenase type 5 in complex with (R)-1-(naphthalen-2-ylsulfonyl)piperidine-3-carboxylic acid (86)==
==Crystal structure of human 17beta-hydroxysteroid dehydrogenase type 5 in complex with (R)-1-(naphthalen-2-ylsulfonyl)piperidine-3-carboxylic acid (86)==
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<StructureSection load='4fa3' size='340' side='right' caption='[[4fa3]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
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<StructureSection load='4fa3' size='340' side='right'caption='[[4fa3]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[4fa3]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4FA3 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4FA3 FirstGlance]. <br>
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<table><tr><td colspan='2'>[[4fa3]] 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=4FA3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4FA3 FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=0SL:(3R)-1-(NAPHTHALEN-2-YLSULFONYL)PIPERIDINE-3-CARBOXYLIC+ACID'>0SL</scene>, <scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene></td></tr>
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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]] 2.2&#8491;</td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4fam|4fam]], [[4fal|4fal]]</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=0SL:(3R)-1-(NAPHTHALEN-2-YLSULFONYL)PIPERIDINE-3-CARBOXYLIC+ACID'>0SL</scene>, <scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene></td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">AKR1C3, DDH1, HSD17B5, KIAA0119, PGFS ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=4fa3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4fa3 OCA], [https://pdbe.org/4fa3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4fa3 RCSB], [https://www.ebi.ac.uk/pdbsum/4fa3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4fa3 ProSAT]</span></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4fa3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4fa3 OCA], [http://pdbe.org/4fa3 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4fa3 RCSB], [http://www.ebi.ac.uk/pdbsum/4fa3 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4fa3 ProSAT]</span></td></tr>
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</table>
</table>
== Function ==
== Function ==
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[[http://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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[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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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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A high-throughput screen identified 3-(3,4-dihydroisoquinolin-2(1H)-ylsulfonyl)benzoic acid as a novel, highly potent (low nM), and isoform-selective (1500-fold) inhibitor of aldo-keto reductase AKR1C3: a target of interest in both breast and prostate cancer. Crystal structure studies showed that the carboxylate group occupies the oxyanion hole in the enzyme, while the sulfonamide provides the correct twist to allow the dihydroisoquinoline to bind in an adjacent hydrophobic pocket. SAR studies around this lead showed that the positioning of the carboxylate was critical, although it could be substituted by acid isosteres and amides. Small substituents on the dihydroisoquinoline gave improvements in potency. A set of "reverse sulfonamides" showed a 12-fold preference for the R stereoisomer. The compounds showed good cellular potency, as measured by inhibition of AKR1C3 metabolism of a known dinitrobenzamide substrate, with a broad rank order between enzymic and cellular activity, but amide analogues were more effective than predicted by the cellular assay.
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3-(3,4-Dihydroisoquinolin-2(1H)-ylsulfonyl)benzoic Acids: Highly Potent and Selective Inhibitors of the Type 5 17-beta-Hydroxysteroid Dehydrogenase AKR1C3.,Jamieson SM, Brooke DG, Heinrich D, Atwell GJ, Silva S, Hamilton EJ, Turnbull AP, Rigoreau LJ, Trivier E, Soudy C, Samlal SS, Owen PJ, Schroeder E, Raynham T, Flanagan JU, Denny WA J Med Chem. 2012 Sep 13;55(17):7746-58. Epub 2012 Aug 21. PMID:22877157<ref>PMID:22877157</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 4fa3" style="background-color:#fffaf0;"></div>
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==See Also==
==See Also==
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*[[Prostaglandin F synthase|Prostaglandin F synthase]]
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*[[Prostaglandin F synthase 3D structures|Prostaglandin F synthase 3D structures]]
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== References ==
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<references/>
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__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Human]]
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[[Category: Homo sapiens]]
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[[Category: Atwell, G J]]
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[[Category: Large Structures]]
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[[Category: Brooke, D G]]
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[[Category: Atwell GJ]]
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[[Category: Denny, W A]]
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[[Category: Brooke DG]]
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[[Category: Flanagan, J U]]
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[[Category: Denny WA]]
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[[Category: Hamilton, E J]]
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[[Category: Flanagan JU]]
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[[Category: Heinrich, D]]
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[[Category: Hamilton EJ]]
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[[Category: Jamieson, S M.F]]
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[[Category: Heinrich D]]
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[[Category: Owen, P J]]
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[[Category: Jamieson SMF]]
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[[Category: Raynham, T]]
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[[Category: Owen PJ]]
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[[Category: Rigoreau, L J.M]]
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[[Category: Raynham T]]
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[[Category: Samlal, S S]]
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[[Category: Rigoreau LJM]]
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[[Category: Schroeder, E]]
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[[Category: Samlal SS]]
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[[Category: Silva, S]]
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[[Category: Schroeder E]]
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[[Category: Soudy, C]]
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[[Category: Silva S]]
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[[Category: Trivier, E]]
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[[Category: Soudy C]]
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[[Category: Turnbull, A P]]
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[[Category: Trivier E]]
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[[Category: Aldo-keto reductase]]
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[[Category: Turnbull AP]]
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[[Category: Oxidoreductase-oxidoreductase inhibitor complex]]
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[[Category: Tim-barrel]]
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Current revision

Crystal structure of human 17beta-hydroxysteroid dehydrogenase type 5 in complex with (R)-1-(naphthalen-2-ylsulfonyl)piperidine-3-carboxylic acid (86)

PDB ID 4fa3

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