3LZ3

Human aldose reductase mutant T113S complexed with IDD388

Summary for 3LZ3

• Entry DOI: 10.2210/pdb3lz3/pdb
• Related: 2IKI 3LBO 3LD5 3LEN 3LEP 3LQG 3LZ5 3M4H
• Descriptor: Aldose reductase, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, (2-{[(4-BROMO-2-FLUOROBENZYL)AMINO]CARBONYL}-5-CHLOROPHENOXY)ACETIC ACID, ... (6 entities in total)
• Functional Keywords: t113s mutant, tim barrel, oxidoreductase, nadp, phosphoprotein, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P15121
• Total number of polymer chains: 1
• Total formula weight: 37316.37

Authors

Koch, C.,Heine, A.,Klebe, G. (deposition date: 2010-03-01, release date: 2010-12-15, Last modification date: 2024-03-20)

Primary citation

Koch, C.,Heine, A.,Klebe, G.
Tracing the detail: how mutations affect binding modes and thermodynamic signatures of closely related aldose reductase inhibitors
J.Mol.Biol., 406:700-712, 2011

PubMed Abstract: 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 Ǻ) 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.

PubMed: 21185307
DOI: 10.1016/j.jmb.2010.11.058

Experimental method

X-RAY DIFFRACTION (1.03 Å)