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| | ==Crystal structure of human AKR1B10 complexed with NADP+ and sulindac== | | ==Crystal structure of human AKR1B10 complexed with NADP+ and sulindac== |
| - | <StructureSection load='4wev' size='340' side='right' caption='[[4wev]], [[Resolution|resolution]] 1.45Å' scene=''> | + | <StructureSection load='4wev' size='340' side='right'caption='[[4wev]], [[Resolution|resolution]] 1.45Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4wev]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4WEV OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4WEV FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4wev]] 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=4WEV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4WEV FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene>, <scene name='pdbligand=SUZ:[(1Z)-5-FLUORO-2-METHYL-1-{4-[METHYLSULFINYL]BENZYLIDENE}-1H-INDEN-3-YL]ACETIC+ACID'>SUZ</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.453Å</td></tr> |
| - | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=MLY:N-DIMETHYL-LYSINE'>MLY</scene>, <scene name='pdbligand=MLZ:N-METHYL-LYSINE'>MLZ</scene></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><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>, <scene name='pdbligand=SUZ:[(1Z)-5-FLUORO-2-METHYL-1-{4-[METHYLSULFINYL]BENZYLIDENE}-1H-INDEN-3-YL]ACETIC+ACID'>SUZ</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1zua|1zua]]</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=4wev FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4wev OCA], [https://pdbe.org/4wev PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4wev RCSB], [https://www.ebi.ac.uk/pdbsum/4wev PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4wev 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=4wev FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4wev OCA], [http://pdbe.org/4wev PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4wev RCSB], [http://www.ebi.ac.uk/pdbsum/4wev PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4wev ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://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> | + | [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;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | ==See Also== | | ==See Also== |
| - | *[[Aldo-keto reductase|Aldo-keto reductase]] | + | *[[Aldo-keto reductase 3D structures|Aldo-keto reductase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Cousido-Siah, A]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Crespo, I]] | + | [[Category: Large Structures]] |
| - | [[Category: Farres, J]] | + | [[Category: Cousido-Siah A]] |
| - | [[Category: Mitschler, A]] | + | [[Category: Crespo I]] |
| - | [[Category: Pares, X]] | + | [[Category: Farres J]] |
| - | [[Category: Podjarny, A]] | + | [[Category: Mitschler A]] |
| - | [[Category: Porte, S]] | + | [[Category: Pares X]] |
| - | [[Category: Ruiz, F X]] | + | [[Category: Podjarny A]] |
| - | [[Category: Aldo-keto reductase]]
| + | [[Category: Porte S]] |
| - | [[Category: Ari]]
| + | [[Category: Ruiz FX]] |
| - | [[Category: Carboxylic type]]
| + | |
| - | [[Category: Cytosolic]]
| + | |
| - | [[Category: Oxidoreductase]]
| + | |
| - | [[Category: Tim barrel]]
| + | |
| Structural highlights
Function
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.[1]
Publication Abstract from PubMed
Aldose reductase (AR, AKR1B1) and AKR1B10 are enzymes implicated in important pathologies (diabetes and cancer) and therefore they have been proposed as suitable targets for drug development. Sulindac is the metabolic precursor of the potent non-steroidal anti-inflammatory drug (NSAID) sulindac sulfide, which suppresses prostaglandin production by inhibition of cyclooxygenases (COX). In addition, sulindac has been found to be one of the NSAIDs with higher antitumoral activity, presumably through COX inhibition. However, sulindac anticancer activity could be partially mediated through COX-independent mechanisms, including the participation of AR and AKR1B10. Previously, it had been shown that sulindac and sulindac sulfone were good AR inhibitors and the structure of the ternary complex with NADP+ and sulindac was described (PDB ID 3U2C). In this work, we determined the three-dimensional structure of AKR1B10 with sulindac and established structure-activity relationships (SAR) of sulindac and their derivatives with AR and AKR1B10. The difference in the IC50 values for sulindac between AR (0.36muM) and AKR1B10 (2.7muM) might be explained by the different positioning and stacking interaction given by Phe122/Phe123, and by the presence of two buried and ordered water molecules in AKR1B10 but not in AR. Moreover, SAR analysis shows that the substitution of the sulfinyl group is structurally allowed in sulindac derivatives. Hence, sulindac and its derivatives emerge as lead compounds for the design of more potent and selective AR and AKR1B10 inhibitors.
Structural analysis of sulindac as an inhibitor of aldose reductase and AKR1B10.,Cousido-Siah A, Ruiz FX, Crespo I, Porte S, Mitschler A, Pares X, Podjarny A, Farres J Chem Biol Interact. 2014 Dec 20. pii: S0009-2797(14)00403-7. doi:, 10.1016/j.cbi.2014.12.018. PMID:25532697[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Gallego O, Ruiz FX, Ardevol A, Dominguez M, Alvarez R, de Lera AR, Rovira C, Farres J, Fita I, Pares X. Structural basis for the high all-trans-retinaldehyde reductase activity of the tumor marker AKR1B10. Proc Natl Acad Sci U S A. 2007 Dec 26;104(52):20764-9. Epub 2007 Dec 17. PMID:18087047
- ↑ Cousido-Siah A, Ruiz FX, Crespo I, Porte S, Mitschler A, Pares X, Podjarny A, Farres J. Structural analysis of sulindac as an inhibitor of aldose reductase and AKR1B10. Chem Biol Interact. 2014 Dec 20. pii: S0009-2797(14)00403-7. doi:, 10.1016/j.cbi.2014.12.018. PMID:25532697 doi:http://dx.doi.org/10.1016/j.cbi.2014.12.018
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