1zua

Crystal Structure Of AKR1B10 Complexed With NADP+ And Tolrestat

spinqualitylabelsall models 1zua, resolution 1.25Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 1zua 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 1.25Å Ligands: NAP, TOL 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. Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMed AKR1B10 is a human aldo-keto reductase (AKR) found to be elevated in several cancer types and in precancerous lesions. In vitro, AKR1B10 exhibits a much higher retinaldehyde reductase activity than any other human AKR, including AKR1B1 (aldose reductase). We here demonstrate that AKR1B10 also acts as a retinaldehyde reductase in vivo. This activity may be relevant in controlling the first step of retinoic acid synthesis. Up-regulation of AKR1B10, resulting in retinoic acid depletion, may lead to cellular proliferation. Both in vitro and in vivo activities of AKR1B10 were inhibited by tolrestat, an AKR1B1 inhibitor developed for diabetes treatment. The crystal structure of the ternary complex AKR1B10-NADP(+)-tolrestat was determined at 1.25-A resolution. Molecular dynamics models of AKR1B10 and AKR1B1 with retinaldehyde isomers and site-directed mutagenesis show that subtle differences at the entrance of the retinoid-binding site, especially at position 125, are determinant for the all-trans-retinaldehyde specificity of AKR1B10. Substitutions in the retinaldehyde cyclohexene ring also influence the specificity. These structural features should facilitate the design of specific inhibitors, with potential use in cancer and diabetes treatments. Structural basis for the high all-trans-retinaldehyde reductase activity of the tumor marker AKR1B10.,Gallego O, Ruiz FX, Ardevol A, Dominguez M, Alvarez R, de Lera AR, Rovira C, Farres J, Fita I, Pares X Proc Natl Acad Sci U S A. 2007 Dec 26;104(52):20764-9. Epub 2007 Dec 17. PMID:18087047 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Aldo-keto reductase 3D structures

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