2pdp | pdb_00002pdp

Human aldose reductase mutant S302R complexed with IDD 393.

spinqualitylabelsall models 2pdp, resolution 1.65Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 2pdp is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 393, NAP Related: 2ikj, 2pd5, 2pd9, 2pdb, 2pdc, 2pdf, 2pdg, 2pdh, 2pdi, 2pdj, 2pdk, 2pdl, 2pdm, 2pdn, 2pdq, 2pdu, 2pdw, 2pdx, 2pdy Gene: ALR2 (HUMAN) 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. 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 Inhibition of human aldose reductase (ALR2) evolved as a promising therapeutic concept to prevent late complications of diabetes. As well as appropriate affinity and bioavailability, putative inhibitors should possess a high level of selectivity for ALR2 over the related aldehyde reductase (ALR1). We investigated the selectivity-determining features by gradually mapping the residues deviating between the binding pockets of ALR1 and ALR2 into the ALR2 binding pocket. The resulting mutational constructs of ALR2 (eight point mutations and one double mutant) were probed for their influence towards ligand selectivity by X-ray structure analysis of the corresponding complexes and isothermal titration calorimetry (ITC). The binding properties of these mutants were evaluated using a ligand set of zopolrestat, a related uracil derivative, IDD388, IDD393, sorbinil, fidarestat and tolrestat. Our study revealed induced-fit adaptations within the mutated binding site as an essential prerequisite for ligand accommodation related to the selectivity discrimination of the ligands. However, our study also highlights the limits of the present understanding of protein-ligand interactions. Interestingly, binding site mutations not involved in any direct interaction to the ligands in various cases show significant effects towards their binding thermodynamics. Furthermore, our results suggest the binding site residues deviating between ALR1 and ALR2 influence ligand affinity in a complex interplay, presumably involving changes of dynamic properties and differences of the solvation/desolvation balance upon ligand binding. Merging the binding sites of aldose and aldehyde reductase for detection of inhibitor selectivity-determining features.,Steuber H, Heine A, Podjarny A, Klebe G J Mol Biol. 2008 Jun 20;379(5):991-1016. Epub 2008 Apr 8. PMID:18495158 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Aldose reductase 3D structures

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