3H4G

Structure of aldehyde reductase holoenzyme in complex with potent aldose reductase inhibitor Fidarestat: Implications for inhibitor binding and selectivity

Replaces:  2AO0

Summary for 3H4G

• Entry DOI: 10.2210/pdb3h4g/pdb
• Related: 1PWM 3CV7
• Descriptor: Alcohol dehydrogenase [NADP+], SULFATE ION, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, ... (5 entities in total)
• Functional Keywords: tim barrel, aldo-keto reductase, ternary complex, nadp, oxidoreductase
• Biological source: Sus scrofa (pigs)
• Total number of polymer chains: 1
• Total formula weight: 37745.65

Authors

Carbone, V.,El-Kabbani, O. (deposition date: 2009-04-20, release date: 2009-05-05, Last modification date: 2023-11-01)

Primary citation

El-Kabbani, O.,Carbone, V.,Darmanin, C.,Oka, M.,Mitschler, A.,Podjarny, A.,Schulze-Briese, C.,Chung, R.P.
Structure of aldehyde reductase holoenzyme in complex with the potent aldose reductase inhibitor fidarestat: implications for inhibitor binding and selectivity
J.Med.Chem., 48:5536-5542, 2005

PubMed Abstract: Structure determination of porcine aldehyde reductase holoenzyme in complex with the potent aldose reductase inhibitor fidarestat was carried out to explain the difference in the potency of the inhibitor for aldose and aldehyde reductases. The hydrogen bonds between the active-site residues Tyr50, His113, and Trp114 and fidarestat are conserved in the two enzymes. In aldose reductase, Leu300 forms a hydrogen bond through its main-chain nitrogen atom with the exocyclic amide group of the inhibitor, which when replaced with a Pro in aldehyde reductase, cannot form a hydrogen bond, thus causing a loss in binding energy. Furthermore, in aldehyde reductase, the side chain of Trp220 occupies a disordered split conformation that is not observed in aldose reductase. Molecular modeling and inhibitory activity measurements suggest that the difference in the interaction between the side chain of Trp220 and fidarestat may contribute to the difference in the binding of the inhibitor to the enzymes.

PubMed: 16107153
DOI: 10.1021/jm050412o

Experimental method

X-RAY DIFFRACTION (1.85 Å)