4xzh: Difference between revisions
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==Crystal structure of human Aldose Reductase complexed with NADP+ and JF0048== | ==Crystal structure of human Aldose Reductase complexed with NADP+ and JF0048== | ||
<StructureSection load='4xzh' size='340' side='right' caption='[[4xzh]], [[Resolution|resolution]] 1.00Å' scene=''> | <StructureSection load='4xzh' size='340' side='right'caption='[[4xzh]], [[Resolution|resolution]] 1.00Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4xzh]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4XZH OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4XZH FirstGlance]. <br> | <table><tr><td colspan='2'>[[4xzh]] 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=4XZH OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4XZH FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=48I:[3-(4-CHLORO-3-NITROBENZYL)-2,4-DIOXO-3,4-DIHYDROPYRIMIDIN-1(2H)-YL]ACETIC+ACID'>48I</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"><scene name='pdbligand=48I:[3-(4-CHLORO-3-NITROBENZYL)-2,4-DIOXO-3,4-DIHYDROPYRIMIDIN-1(2H)-YL]ACETIC+ACID'>48I</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene></td></tr> | ||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1us0|1us0]]</td></tr> | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1us0|1us0]]</td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">AKR1B1, ALDR1 ([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/Aldehyde_reductase Aldehyde reductase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.1.1.21 1.1.1.21] </span></td></tr> | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Aldehyde_reductase Aldehyde reductase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.1.1.21 1.1.1.21] </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=4xzh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4xzh OCA], [http://pdbe.org/4xzh PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4xzh RCSB], [http://www.ebi.ac.uk/pdbsum/4xzh 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=4xzh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4xzh OCA], [http://pdbe.org/4xzh PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4xzh RCSB], [http://www.ebi.ac.uk/pdbsum/4xzh PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4xzh ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == Function == | ||
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</div> | </div> | ||
<div class="pdbe-citations 4xzh" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 4xzh" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[Aldose reductase 3D structures|Aldose reductase 3D structures]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
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</StructureSection> | </StructureSection> | ||
[[Category: Aldehyde reductase]] | [[Category: Aldehyde reductase]] | ||
[[Category: Human]] | |||
[[Category: Large Structures]] | |||
[[Category: Cousido-Siah, A]] | [[Category: Cousido-Siah, A]] | ||
[[Category: Dominguez, M]] | [[Category: Dominguez, M]] | ||
Revision as of 02:34, 6 June 2019
Crystal structure of human Aldose Reductase complexed with NADP+ and JF0048Crystal structure of human Aldose Reductase complexed with NADP+ and JF0048
Structural highlights
Function[ALDR_HUMAN] Catalyzes the NADPH-dependent reduction of a wide variety of carbonyl-containing compounds to their corresponding alcohols with a broad range of catalytic efficiencies. Publication Abstract from PubMedThe human enzymes aldose reductase (AR) and AKR1B10 have been thoroughly explored in terms of their roles in diabetes, inflammatory disorders, and cancer. In this study we identified two new lead compounds, 2-(3-(4-chloro-3-nitrobenzyl)-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetic acid (JF0048, 3) and 2-(2,4-dioxo-3-(2,3,4,5-tetrabromo-6-methoxybenzyl)-3,4-dihydropyrimidin-1(2H)-yl )acetic acid (JF0049, 4), which selectively target these enzymes. Although 3 and 4 share the 3-benzyluracil-1-acetic acid scaffold, they have different substituents in their aryl moieties. Inhibition studies along with thermodynamic and structural characterizations of both enzymes revealed that the chloronitrobenzyl moiety of compound 3 can open the AR specificity pocket but not that of the AKR1B10 cognate. In contrast, the larger atoms at the ortho and/or meta positions of compound 4 prevent the AR specificity pocket from opening due to steric hindrance and provide a tighter fit to the AKR1B10 inhibitor binding pocket, probably enhanced by the displacement of a disordered water molecule trapped in a hydrophobic subpocket, creating an enthalpic signature. Furthermore, this selectivity also occurs in the cell, which enables the development of a more efficient drug design strategy: compound 3 prevents sorbitol accumulation in human retinal ARPE-19 cells, whereas 4 stops proliferation in human lung cancer NCI-H460 cells. Structural Determinants of the Selectivity of 3-Benzyluracil-1-acetic Acids toward Human Enzymes Aldose Reductase and AKR1B10.,Ruiz FX, Cousido-Siah A, Porte S, Dominguez M, Crespo I, Rechlin C, Mitschler A, de Lera AR, Martin MJ, de la Fuente JA, Klebe G, Pares X, Farres J, Podjarny A ChemMedChem. 2015 Nov 9. doi: 10.1002/cmdc.201500393. PMID:26549844[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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