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| | ==Crystal structure of human 17beta-hydroxysteroid dehydrogenase type 5 (AKR1C3) in complex with NADP+ and 2'-desmethyl-indomethacin== | | ==Crystal structure of human 17beta-hydroxysteroid dehydrogenase type 5 (AKR1C3) in complex with NADP+ and 2'-desmethyl-indomethacin== |
| - | <StructureSection load='4dbw' size='340' side='right' caption='[[4dbw]], [[Resolution|resolution]] 1.80Å' scene=''> | + | <StructureSection load='4dbw' size='340' side='right'caption='[[4dbw]], [[Resolution|resolution]] 1.80Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4dbw]] is a 2 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=4DBW OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4DBW FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4dbw]] is a 2 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=4DBW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4DBW FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=511:[1-(4-CHLOROBENZOYL)-5-METHOXY-1H-INDOL-3-YL]ACETIC+ACID'>511</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=511:[1-(4-CHLOROBENZOYL)-5-METHOXY-1H-INDOL-3-YL]ACETIC+ACID'>511</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene></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 id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4dbw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4dbw OCA], [https://pdbe.org/4dbw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4dbw RCSB], [https://www.ebi.ac.uk/pdbsum/4dbw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4dbw ProSAT]</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=4dbw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4dbw OCA], [http://pdbe.org/4dbw PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4dbw RCSB], [http://www.ebi.ac.uk/pdbsum/4dbw PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4dbw ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == 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. | + | [[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. |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Chen, M]] | + | [[Category: Large Structures]] |
| - | [[Category: Christianson, D W]] | + | [[Category: Chen M]] |
| - | [[Category: Marnett, L J]]
| + | [[Category: Christianson DW]] |
| - | [[Category: Penning, T M]]
| + | [[Category: Marnett LJ]] |
| - | [[Category: Akr1c3 selective inhibitor]] | + | [[Category: Penning TM]] |
| - | [[Category: Castrate resistant prostate cancer]] | + | |
| - | [[Category: Oxidoreductase-oxidoreductase inhibitor complex]] | + | |
| - | [[Category: Steroid metabolism]]
| + | |
| - | [[Category: Tim barrel]]
| + | |
| 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 PubMed
Castrate-resistant prostate cancer (CRPC) is a fatal, metastatic form of prostate cancer. CRPC is characterized by reactivation of the androgen axis due to changes in androgen receptor signaling and/or adaptive intratumoral androgen biosynthesis. AKR1C3 is upregulated in CRPC where it catalyzes the formation of potent androgens. This makes AKR1C3 a target for the treatment of CRPC. AKR1C3 inhibitors should not inhibit AKR1C1/AKR1C2, which inactivate 5alpha-dihydrotestosterone. Indomethacin, used to inhibit cyclooxygenase, also inhibits AKR1C3 and displays selectivity over AKR1C1/AKR1C2. Parallel synthetic strategies were used to generate libraries of indomethacin analogues, which exhibit reduced cyclooxygenase inhibitory activity but retain AKR1C3 inhibitory potency and selectivity. The lead compounds inhibited AKR1C3 with nanomolar potency, displayed >100-fold selectivity over AKR1C1/AKR1C2, and blocked testosterone formation in LNCaP-AKR1C3 cells. The AKR1C3.NADP(+).2'-des-methyl-indomethacin crystal structure was determined, and it revealed a unique inhibitor binding mode. The compounds reported are promising agents for the development of therapeutics for CRPC.
Development of potent and selective indomethacin analogues for the inhibition of AKR1C3 (Type 5 17beta-hydroxysteroid dehydrogenase/prostaglandin F synthase) in castrate-resistant prostate cancer.,Liedtke AJ, Adeniji AO, Chen M, Byrns MC, Jin Y, Christianson DW, Marnett LJ, Penning TM J Med Chem. 2013 Mar 28;56(6):2429-46. doi: 10.1021/jm3017656. Epub 2013 Mar 13. PMID:23432095[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Liedtke AJ, Adeniji AO, Chen M, Byrns MC, Jin Y, Christianson DW, Marnett LJ, Penning TM. Development of potent and selective indomethacin analogues for the inhibition of AKR1C3 (Type 5 17beta-hydroxysteroid dehydrogenase/prostaglandin F synthase) in castrate-resistant prostate cancer. J Med Chem. 2013 Mar 28;56(6):2429-46. doi: 10.1021/jm3017656. Epub 2013 Mar 13. PMID:23432095 doi:10.1021/jm3017656
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