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2ISF

Crystal Structure of C298A W219Y Aldose Reductase complexed with Phenylacetic Acid

Summary for 2ISF
Entry DOI10.2210/pdb2isf/pdb
Related2INE 2INZ 2IPW 2IQ0 2IQD 2IS7
DescriptorAldose reductase, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, 2-PHENYLACETIC ACID, ... (4 entities in total)
Functional Keywordstim-barrel, ari, aldo-keto reductase, oxidoreductase
Biological sourceHomo sapiens (human)
Cellular locationCytoplasm: P15121
Total number of polymer chains1
Total formula weight36591.60
Authors
Harrison, D.H.T.,Pape, E.,Brownlee, J.M. (deposition date: 2006-10-17, release date: 2006-11-28, Last modification date: 2023-08-30)
Primary citationBrownlee, J.M.,Carlson, E.,Milne, A.C.,Pape, E.,Harrison, D.H.
Structural and thermodynamic studies of simple aldose reductase-inhibitor complexes.
Bioorg.Chem., 34:424-444, 2006
Cited by
PubMed Abstract: The competitive inhibition constants of series of inhibitors related to phenylacetic acid against both wild-type and the doubly mutanted C298A/W219Y aldose reductase have been measured. Van't Hoff analysis shows that these acids bind with an enthalpy near -6.8 kcal/mol derived from the electrostatic interactions, while the 100-fold differences in binding affinity appear to be largely due to entropic factors that result from differences in conformational freedom in the unbound state. These temperature studies also point out the difference between substrate and inhibitor binding. X-ray crystallographic analysis of a few of these inhibitor complexes both confirms the importance of a previously described anion binding site and reveals the hydrophobic nature of the primary binding site and its general plasticity. Based on these results, N-glycylthiosuccinimides were synthesized to demonstrate their potential in studies that probe distal binding sites. Reduced alpha-lipoic acid, an anti-oxidant and therapeutic for diabetic complications, was shown to bind aldose reductase with a binding constant of 1 microM.
PubMed: 17083960
DOI: 10.1016/j.bioorg.2006.09.004
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (2 Å)
Structure validation

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