6a7a
From Proteopedia
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<StructureSection load='6a7a' size='340' side='right'caption='[[6a7a]], [[Resolution|resolution]] 2.37Å' scene=''> | <StructureSection load='6a7a' size='340' side='right'caption='[[6a7a]], [[Resolution|resolution]] 2.37Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>[[6a7a]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6A7A OCA]. For a <b>guided tour on the structure components</b> use [http:// | + | <table><tr><td colspan='2'>[[6a7a]] 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=6A7A OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6A7A FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=9S0:(4R)-6-amino-4-(4-hydroxy-3-methoxy-5-nitrophenyl)-3-propyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile'>9S0</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=9S0:(4R)-6-amino-4-(4-hydroxy-3-methoxy-5-nitrophenyl)-3-propyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile'>9S0</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http:// | + | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">AKR1C1, DDH, DDH1 ([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'>[http://proteopedia.org/fgij/fg.htm?mol=6a7a FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6a7a OCA], [http://pdbe.org/6a7a PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6a7a RCSB], [http://www.ebi.ac.uk/pdbsum/6a7a PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6a7a ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == Function == | ||
[[http://www.uniprot.org/uniprot/AK1C1_HUMAN AK1C1_HUMAN]] Converts progesterone to its inactive form, 20-alpha-dihydroxyprogesterone (20-alpha-OHP). In the liver and intestine, may have a role in the transport of bile. May have a role in monitoring the intrahepatic bile acid concentration. Has a low bile-binding ability. May play a role in myelin formation.<ref>PMID:11013348</ref> <ref>PMID:8573067</ref> | [[http://www.uniprot.org/uniprot/AK1C1_HUMAN AK1C1_HUMAN]] Converts progesterone to its inactive form, 20-alpha-dihydroxyprogesterone (20-alpha-OHP). In the liver and intestine, may have a role in the transport of bile. May have a role in monitoring the intrahepatic bile acid concentration. Has a low bile-binding ability. May play a role in myelin formation.<ref>PMID:11013348</ref> <ref>PMID:8573067</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | AKR1C3 is a promising therapeutic target for castration-resistant prostate cancer. Herein, an evaluation of in-house library discovered substituted pyranopyrazole as a novel scaffold for AKR1C3 inhibitors. Preliminary SAR exploration identified its derivative 19d as the most promising compound with an IC50 of 0.160muM among the 23 synthesized molecules. Crystal structure studies revealed that the binding mode of the pyranopyrazole scaffold is different from the current inhibitors. Hydroxyl, methoxy and nitro group at the C4-phenyl substituent together anchor the inhibitor to the oxyanion site, while the core of the scaffold dramatically enlarges but partially occupies the SP pockets with abundant hydrogen bond interactions. Strikingly, the inhibitor undergoes a conformational change to fit AKR1C3 and its homologous protein AKR1C1. Our results suggested that conformational changes of the receptor and the inhibitor should both be considered during the rational design of selective AKR1C3 inhibitors. Detailed binding features obtained from molecular dynamics simulations helped to finally elucidate the molecular basis of 6-amino-4-phenyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitriles as AKR1C3 inhibitors, which would facilitate the future rational inhibitor design and structural optimization. | ||
| + | |||
| + | Screening, synthesis, crystal structure, and molecular basis of 6-amino-4-phenyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitriles as novel AKR1C3 inhibitors.,Zheng X, Jiang Z, Li X, Zhang C, Li Z, Wu Y, Wang X, Zhang C, Luo HB, Xu J, Wu D Bioorg Med Chem. 2018 Dec 1;26(22):5934-5943. doi: 10.1016/j.bmc.2018.10.044., Epub 2018 Nov 3. PMID:30429100<ref>PMID:30429100</ref> | ||
| + | |||
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 6a7a" style="background-color:#fffaf0;"></div> | ||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
| + | [[Category: Human]] | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Chen, Y]] | [[Category: Chen, Y]] | ||
Revision as of 06:55, 29 April 2020
AKR1C1 complexed with new inhibitor with novel scaffold
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