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| | ==Crystal structure of human AKR1B10 complexed with NADP+ and JF0064== | | ==Crystal structure of human AKR1B10 complexed with NADP+ and JF0064== |
| - | <StructureSection load='4icc' size='340' side='right' caption='[[4icc]], [[Resolution|resolution]] 1.75Å' scene=''> | + | <StructureSection load='4icc' size='340' side='right'caption='[[4icc]], [[Resolution|resolution]] 1.75Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4icc]] 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=4ICC OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4ICC FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4icc]] 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=4ICC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4ICC FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=64I:2,2,3,3,5,5,6,6-OCTAFLUOROBIPHENYL-4,4-DIOL'>64I</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</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]] 1.752Å</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=64I:2,2,3,3,5,5,6,6-OCTAFLUOROBIPHENYL-4,4-DIOL'>64I</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='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1zua|1zua]], [[4icf|4icf]], [[4igs|4igs]], [[4ice|4ice]]</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=4icc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4icc OCA], [https://pdbe.org/4icc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4icc RCSB], [https://www.ebi.ac.uk/pdbsum/4icc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4icc ProSAT]</span></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">AKR1B10, AKR1B11 ([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://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4icc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4icc OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4icc RCSB], [http://www.ebi.ac.uk/pdbsum/4icc PDBsum]</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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| | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| | </div> | | </div> |
| | + | <div class="pdbe-citations 4icc" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==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: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Cousido-Siah, A]] | + | [[Category: Large Structures]] |
| - | [[Category: Farres, J]] | + | [[Category: Cousido-Siah A]] |
| - | [[Category: Fuente, J A.de la]] | + | [[Category: Farres J]] |
| - | [[Category: Klebe, G]] | + | [[Category: Klebe G]] |
| - | [[Category: Lera, A R.de]]
| + | [[Category: Martin MJ]] |
| - | [[Category: Martin, M J]] | + | [[Category: Mitschler A]] |
| - | [[Category: Mitschler, A]] | + | [[Category: Pares X]] |
| - | [[Category: Pares, X]] | + | [[Category: Podjarny A]] |
| - | [[Category: Podjarny, A]] | + | [[Category: Porte S]] |
| - | [[Category: Porte, S]] | + | [[Category: Ruiz FX]] |
| - | [[Category: Ruiz, F X]] | + | [[Category: De Lera AR]] |
| - | [[Category: Aldo-keto reductase]] | + | [[Category: De la Fuente JA]] |
| - | [[Category: Cytosolic]] | + | |
| - | [[Category: Halogenated compound]]
| + | |
| - | [[Category: Oxidoreductase]]
| + | |
| - | [[Category: Oxidoreductase-oxidoreductase inhibitor complex]]
| + | |
| - | [[Category: Tim barrel]]
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| 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
Aldo-keto reductases (AKRs) are mostly monomeric enzymes which fold into a highly conserved (alpha/beta)8 barrel, while their substrate specificity and inhibitor selectivity are determined by interaction with residues located in three highly variable external loops. The closely related human enzymes aldose reductase (AR or AKR1B1) and AKR1B10 are of biomedical interest because of their involvement in secondary diabetic complications (AR) and in cancer, e.g. hepatocellular carcinoma and smoking-related lung cancer (AKR1B10). After characterization of the IC50 values of both AKRs with a series of polyhalogenated compounds, 2,2',3,3',5,5',6,6'-octafluoro-4,4'-biphenyldiol (JF0064) was identified as a lead inhibitor of both enzymes with a new scaffold (a 1,1'-biphenyl-4,4'-diol). An ultrahigh-resolution X-ray structure of the AR-NADP(+)-JF0064 complex has been determined at 0.85 A resolution, allowing it to be observed that JF0064 interacts with the catalytic residue Tyr48 through a negatively charged hydroxyl group (i.e. the acidic phenol). The non-competitive inhibition pattern observed for JF0064 with both enzymes suggests that this acidic hydroxyl group is also present in the case of AKR1B10. Moreover, the combination of surface lysine methylation and the introduction of K125R and V301L mutations enabled the determination of the X-ray crystallographic structure of the corresponding AKR1B10-NADP(+)-JF0064 complex. Comparison of the two structures has unveiled some important hints for subsequent structure-based drug-design efforts.
Identification of a novel polyfluorinated compound as a lead to inhibit the human enzymes aldose reductase and AKR1B10: structure determination of both ternary complexes and implications for drug design.,Cousido-Siah A, Ruiz FX, Mitschler A, Porte S, de Lera AR, Martin MJ, Manzanaro S, de la Fuente JA, Terwesten F, Betz M, Klebe G, Farres J, Pares X, Podjarny A Acta Crystallogr D Biol Crystallogr. 2014 Mar;70(Pt 3):889-903. doi:, 10.1107/S1399004713033452. Epub 2014 Feb 27. PMID:24598757[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, Mitschler A, Porte S, de Lera AR, Martin MJ, Manzanaro S, de la Fuente JA, Terwesten F, Betz M, Klebe G, Farres J, Pares X, Podjarny A. Identification of a novel polyfluorinated compound as a lead to inhibit the human enzymes aldose reductase and AKR1B10: structure determination of both ternary complexes and implications for drug design. Acta Crystallogr D Biol Crystallogr. 2014 Mar;70(Pt 3):889-903. doi:, 10.1107/S1399004713033452. Epub 2014 Feb 27. PMID:24598757 doi:http://dx.doi.org/10.1107/S1399004713033452
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