7c7g: Difference between revisions
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==Crystal structures of AKR1C3 ternary complex with NADP+ and the chromene derivative 2j== | ==Crystal structures of AKR1C3 ternary complex with NADP+ and the chromene derivative 2j== | ||
<StructureSection load='7c7g' size='340' side='right'caption='[[7c7g]]' scene=''> | <StructureSection load='7c7g' size='340' side='right'caption='[[7c7g]], [[Resolution|resolution]] 1.86Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7C7G OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=7C7G FirstGlance]. <br> | <table><tr><td colspan='2'>[[7c7g]] 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=7C7G OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=7C7G FirstGlance]. <br> | ||
</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=7c7g FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7c7g OCA], [http://pdbe.org/7c7g PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=7c7g RCSB], [http://www.ebi.ac.uk/pdbsum/7c7g PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=7c7g ProSAT]</span></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FJR:2-azanylidene-N-(4-methylphenyl)-8-oxidanyl-chromene-3-carboxamide'>FJR</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='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Trans-1,2-dihydrobenzene-1,2-diol_dehydrogenase Trans-1,2-dihydrobenzene-1,2-diol dehydrogenase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.3.1.20 1.3.1.20] </span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=7c7g FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7c7g OCA], [http://pdbe.org/7c7g PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=7c7g RCSB], [http://www.ebi.ac.uk/pdbsum/7c7g PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=7c7g ProSAT]</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;"> | |||
== Publication Abstract from PubMed == | |||
Aldo-keto reductase (AKR) 1C3 catalyzes the synthesis of active androgens that promote the progression of prostate cancer. AKR1C3 also contributes to androgen-independent cell proliferation and survival through the metabolism of prostaglandins and reactive aldehydes. Because of its elevation in castration-resistant prostate cancer (CRPC) tissues, AKR1C3 is a promising therapeutic target for CRPC. In this study, we found a novel potent AKR1C3 inhibitor, N-(4-fluorophenyl)-8-hydroxy-2-imino-2H-chromene-3-carboxamide (2d), and synthesized its derivatives with IC50 values of 25-56 nM and >220-fold selectivity over other AKRs (1C1, 1C2, and 1C4). The structural factors for the inhibitory potency were elucidated by crystallographic study of AKR1C3 complexes with 2j and 2l. The inhibitors suppressed proliferation of prostate cancer 22Rv1 and PC3 cells through both androgen-dependent and androgen-independent mechanisms. Additionally, 2j and 2l prevented prostate tumor growth in a xenograft mouse model. Furthermore, the inhibitors significantly augmented apoptotic cell death induced by anti-CRPC drugs (abiraterone or enzalutamide). | |||
Development of Novel AKR1C3 Inhibitors as New Potential Treatment for Castration-Resistant Prostate Cancer.,Endo S, Oguri H, Segawa J, Kawai M, Hu D, Xia S, Okada T, Irie K, Fujii S, Gouda H, Iguchi K, Matsukawa T, Fujimoto N, Nakayama T, Toyooka N, Matsunaga T, Ikari A J Med Chem. 2020 Sep 9. doi: 10.1021/acs.jmedchem.0c00939. PMID:32847363<ref>PMID:32847363</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7c7g" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Human]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Endo S]] | [[Category: Trans-1,2-dihydrobenzene-1,2-diol dehydrogenase]] | ||
[[Category: Irie K]] | [[Category: Endo, S]] | ||
[[Category: Toyooka N]] | [[Category: Irie, K]] | ||
[[Category: Toyooka, N]] | |||
[[Category: Cancer]] | |||
[[Category: Oxidoreductase]] | |||
Revision as of 09:43, 7 October 2020
Crystal structures of AKR1C3 ternary complex with NADP+ and the chromene derivative 2jCrystal structures of AKR1C3 ternary complex with NADP+ and the chromene derivative 2j
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 PubMedAldo-keto reductase (AKR) 1C3 catalyzes the synthesis of active androgens that promote the progression of prostate cancer. AKR1C3 also contributes to androgen-independent cell proliferation and survival through the metabolism of prostaglandins and reactive aldehydes. Because of its elevation in castration-resistant prostate cancer (CRPC) tissues, AKR1C3 is a promising therapeutic target for CRPC. In this study, we found a novel potent AKR1C3 inhibitor, N-(4-fluorophenyl)-8-hydroxy-2-imino-2H-chromene-3-carboxamide (2d), and synthesized its derivatives with IC50 values of 25-56 nM and >220-fold selectivity over other AKRs (1C1, 1C2, and 1C4). The structural factors for the inhibitory potency were elucidated by crystallographic study of AKR1C3 complexes with 2j and 2l. The inhibitors suppressed proliferation of prostate cancer 22Rv1 and PC3 cells through both androgen-dependent and androgen-independent mechanisms. Additionally, 2j and 2l prevented prostate tumor growth in a xenograft mouse model. Furthermore, the inhibitors significantly augmented apoptotic cell death induced by anti-CRPC drugs (abiraterone or enzalutamide). Development of Novel AKR1C3 Inhibitors as New Potential Treatment for Castration-Resistant Prostate Cancer.,Endo S, Oguri H, Segawa J, Kawai M, Hu D, Xia S, Okada T, Irie K, Fujii S, Gouda H, Iguchi K, Matsukawa T, Fujimoto N, Nakayama T, Toyooka N, Matsunaga T, Ikari A J Med Chem. 2020 Sep 9. doi: 10.1021/acs.jmedchem.0c00939. PMID:32847363[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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