4xzn

Crystal structure of the methylated K125R/V301L AKR1B10 Holoenzyme

spinqualitylabelsall models 4xzn, resolution 1.70Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4xzn is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.7Å Ligands: EDO, MLY, MLZ, NAP Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT 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. 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Aldo-keto reductase 3D structures

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