4h7c: Difference between revisions
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== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4h7c]] 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=4H7C OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4H7C FirstGlance]. <br> | <table><tr><td colspan='2'>[[4h7c]] 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=4H7C OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4H7C FirstGlance]. <br> | ||
</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=10H:1-(4-{[(2R)-2-METHYLPIPERIDIN-1-YL]SULFONYL}PHENYL)-1,3-DIHYDRO-2H-PYRROL-2-ONE'>10H</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene>< | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=10H:1-(4-{[(2R)-2-METHYLPIPERIDIN-1-YL]SULFONYL}PHENYL)-1,3-DIHYDRO-2H-PYRROL-2-ONE'>10H</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene></td></tr> | ||
<tr><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> | <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> | ||
<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4h7c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4h7c OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4h7c RCSB], [http://www.ebi.ac.uk/pdbsum/4h7c PDBsum]</span></td></tr> | <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=4h7c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4h7c OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4h7c RCSB], [http://www.ebi.ac.uk/pdbsum/4h7c PDBsum]</span></td></tr> | ||
<table> | </table> | ||
== Function == | |||
[[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. | |||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
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</StructureSection> | </StructureSection> | ||
[[Category: Human]] | [[Category: Human]] | ||
[[Category: Denny, W A | [[Category: Denny, W A]] | ||
[[Category: Flanagan, J U | [[Category: Flanagan, J U]] | ||
[[Category: Heinrich, D | [[Category: Heinrich, D]] | ||
[[Category: Jamieson, S M.F | [[Category: Jamieson, S M.F]] | ||
[[Category: Owen, P J | [[Category: Owen, P J]] | ||
[[Category: Raynham, T | [[Category: Raynham, T]] | ||
[[Category: Rigoreau, L J.M | [[Category: Rigoreau, L J.M]] | ||
[[Category: Samlal, S S | [[Category: Samlal, S S]] | ||
[[Category: Schroeder, E | [[Category: Schroeder, E]] | ||
[[Category: Silva, S | [[Category: Silva, S]] | ||
[[Category: Soudy, C | [[Category: Soudy, C]] | ||
[[Category: Trivier, E | [[Category: Trivier, E]] | ||
[[Category: Turnbull, A P | [[Category: Turnbull, A P]] | ||
[[Category: Aldo-keto reductase]] | [[Category: Aldo-keto reductase]] | ||
[[Category: Oxidoreductase-oxidoreductase inhibitor complex]] | [[Category: Oxidoreductase-oxidoreductase inhibitor complex]] | ||
[[Category: Tim-barrel]] | [[Category: Tim-barrel]] | ||
Revision as of 12:07, 25 December 2014
Crystal structure of human 17beta-hydroxysteroid dehydrogenase type 5 in complex with 1-{4-[(2-methyl-1-piperidinyl)sulfonyl]phenyl}-2-pyrrolidinoneCrystal structure of human 17beta-hydroxysteroid dehydrogenase type 5 in complex with 1-{4-[(2-methyl-1-piperidinyl)sulfonyl]phenyl}-2-pyrrolidinone
Structural highlights
Function[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. Publication Abstract from PubMedHigh expression of the aldo-keto reductase enzyme AKR1C3 in the human prostate and breast has implicated it in the development and progression of leukemias and of prostate and breast cancers. Inhibitors are thus of interest as potential drugs. Most inhibitors of AKR1C3 are carboxylic acids, whose transport into cells is likely dominated by carrier-mediated processes. We describe here a series of (piperidinosulfonamidophenyl)pyrrolidin-2-ones as potent (<100 nM) and isoform-selective non-carboxylate inhibitors of AKR1C3. Structure-activity relationships identified the sulfonamide was critical, and a crystal structure showed the 2-pyrrolidinone does not interact directly with residues in the oxyanion hole. Variations in the position, co-planarity or electronic nature of the pyrrolidinone ring severely diminished activity, as did altering the size or polarity of the piperidino ring. There was a broad correlation between the enzyme potencies of the compounds and their effectiveness at inhibiting AKR1C3 activity in cells. Synthesis and structure-activity relationships for 1-(4-(piperidin-1-ylsulfonyl)phenyl)pyrrolidin-2-ones as novel non-carboxylate inhibitors of the aldo-keto reductase enzyme AKR1C3.,Heinrich DM, Flanagan JU, Jamieson SM, Silva S, Rigoreau LJ, Trivier E, Raynham T, Turnbull AP, Denny WA Eur J Med Chem. 2013 Feb 9;62C:738-744. doi: 10.1016/j.ejmech.2013.01.047. PMID:23454516[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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