6f84

AKR1B1 at 2.55 MGy radiation dose.

spinqualitylabelsall models 6f84, resolution 1.09Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6f84 is a 1 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: CIT, NAP Related: 6f7r, 6f81, 6f82, 6f8o Activity: Aldehyde reductase, with EC number 1.1.1.21 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [ALDR_HUMAN] Catalyzes the NADPH-dependent reduction of a wide variety of carbonyl-containing compounds to their corresponding alcohols with a broad range of catalytic efficiencies. Publication Abstract from PubMed Human aldose reductase (hAR, AKR1B1) has been explored as drug target since the 1980s for its implication in diabetic complications. An activated form of hAR was found in cells from diabetic patients, showing a reduced sensitivity to inhibitors in clinical trials, which may prevent its pharmacological use. Here we report the conversion of native hAR to its activated form by X-ray irradiation simulating oxidative stress conditions. Upon irradiation, the enzyme activity increases moderately and the potency of several hAR inhibitors decay before global protein radiation damage appears. The catalytic behavior of activated hAR is also reproduced as the KM increases dramatically while the kcat is not much affected. Consistently, the catalytic tetrad is not showing any modification. The only catalytically-relevant structural difference observed is the conversion of residue Cys298 to serine and alanine. A mechanism involving electron capture is suggested for the hAR activation. We propose that hAR inhibitors should not be designed against the native protein but against the activated form as obtained from X-ray irradiation. Furthermore, since the reactive species produced under irradiation conditions are the same as those produced under oxidative stress, the described irradiation method can be applied to other relevant proteins under oxidative stress environments. Efficacy of aldose reductase inhibitors is affected by oxidative stress induced under X-ray irradiation.,Castellvi A, Crespo I, Crosas E, Camara-Artigas A, Gavira JA, Aranda MAG, Pares X, Farres J, Juanhuix J Sci Rep. 2019 Feb 28;9(1):3177. doi: 10.1038/s41598-019-39722-0. PMID:30816220 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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