2PDW

Human aldose reductase mutant C303D complexed with fidarestat.

Summary for 2PDW

• Entry DOI: 10.2210/pdb2pdw/pdb
• Related: 1PWM 2PD5 2PD9 2PDB 2PDC 2PDF 2PDG 2PDH 2PDI 2PDJ 2PDK 2PDL 2PDM 2PDN 2PDP 2PDQ 2PDU 2PDX 2PDY
• Descriptor: Aldose reductase, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, (2S,4S)-2-AMINOFORMYL-6-FLUORO-SPIRO[CHROMAN-4,4'-IMIDAZOLIDINE]-2',5'-DIONE, ... (4 entities in total)
• Functional Keywords: tim barrel, oxidoreductase
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P15121
• Total number of polymer chains: 1
• Total formula weight: 36932.91

Authors

Steuber, H.,Heine, A.,Klebe, G. (deposition date: 2007-04-01, release date: 2008-04-01, Last modification date: 2023-08-30)

Primary citation

Steuber, H.,Heine, A.,Podjarny, A.,Klebe, G.
Merging the binding sites of aldose and aldehyde reductase for detection of inhibitor selectivity-determining features.
J.Mol.Biol., 379:991-1016, 2008

PubMed Abstract: 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.

PubMed: 18495158
DOI: 10.1016/j.jmb.2008.03.063

Experimental method

X-RAY DIFFRACTION (1.55 Å)