3lep

Human Aldose Reductase mutant T113C in complex with IDD388

spinqualitylabelsall models 3lep, resolution 0.99Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3lep 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. Ligands: 388, BR, CIT, NAP Related: 2iki, 3lbo, 1us0, 3ld5, 3lqg, 3lz3, 3m4h, 3lql, 3lz5 Gene: alr2 (Homo sapiens) Activity: Aldehyde reductase, with EC number 1.1.1.21 Resources: FirstGlance, OCA, RCSB, PDBsum 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 Improvements on the computational methods for affinity prediction from the structure of protein-ligand complexes require a better understanding of the nature of molecular interactions and biomolecular recognition principles. In the present contribution, the binding of two chemically closely related human aldose reductase inhibitors had been studied by high-resolution X-ray analysis (0.92-1.35 A) and isothermal titration calorimetry against a series of single-site mutants of the wild-type protein. A crucial threonine thought to be involved in a short bromine-to-oxygen halogen bond to the inhibitors in the wild type has been mutated to the structurally similar residues alanine, cysteine, serine and valine. Overall, structurally, the binding mode of the inhibitors is conserved; however, small but significant geometrical adaptations are observed as a consequence of the spatial and electronic changes at the mutation site. They involve the opening of a central bond angle and shifts in consequence of the lost or gained halogen bonds. Remarkably, the tiny structural changes are responded by partly strong modulation of the thermodynamic profiles. Even though the free energy of binding is maximally perturbed by only 7 kJ/mol, much stronger modulations and shifts in the enthalpy and entropy signatures are revealed, which indicate a pronounced enthalpy/entropy compensation. However, an explanatory correlation can be detected when facing these perturbances against the small structural changes. This also provides deeper insights into how single-site mutations can alter the selectivity profile of closely related ligands against a target protein. Tracing the detail: how mutations affect binding modes and thermodynamic signatures of closely related aldose reductase inhibitors.,Koch C, Heine A, Klebe G J Mol Biol. 2011 Mar 11;406(5):700-12. Epub 2010 Dec 23. PMID:21185307 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Aldose Reductase

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