View source for 4xzl


==Crystal structure of human AKR1B10 complexed with NADP+ and JF0049==
<StructureSection load='4xzl' size='340' side='right'caption='[[4xzl]], [[Resolution|resolution]] 1.70&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4xzl]] is a 1 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=4XZL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4XZL FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.7&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=F49:[2,4-DIOXO-3-(2,3,4,5-TETRABROMO-6-METHOXYBENZYL)-3,4-DIHYDROPYRIMIDIN-1(2H)-YL]ACETIC+ACID'>F49</scene>, <scene name='pdbligand=MLY:N-DIMETHYL-LYSINE'>MLY</scene>, <scene name='pdbligand=MLZ:N-METHYL-LYSINE'>MLZ</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'>[https://proteopedia.org/fgij/fg.htm?mol=4xzl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4xzl OCA], [https://pdbe.org/4xzl PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4xzl RCSB], [https://www.ebi.ac.uk/pdbsum/4xzl PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4xzl ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/AK1BA_HUMAN AK1BA_HUMAN] Acts as all-trans-retinaldehyde reductase. Can efficiently reduce aliphatic and aromatic aldehydes, and is less active on hexoses (in vitro). May be responsible for detoxification of reactive aldehydes in the digested food before the nutrients are passed on to other organs.<ref>PMID:18087047</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The 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<ref>PMID:26549844</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4xzl" style="background-color:#fffaf0;"></div>

==See Also==
*[[Aldo-keto reductase 3D structures|Aldo-keto reductase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Cousido-Siah A]]
[[Category: Dominguez M]]
[[Category: Farres J]]
[[Category: Mitschler A]]
[[Category: Pares X]]
[[Category: Podjarny A]]
[[Category: Ruiz FX]]
[[Category: De Lera AR]]