1T40

Crystal structure of human aldose reductase complexed with NADP and IDD552 at ph 5

Summary for 1T40

• Entry DOI: 10.2210/pdb1t40/pdb
• Related: 1T41
• Descriptor: Aldose reductase, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, [5-FLUORO-2-({[(4,5,7-TRIFLUORO-1,3-BENZOTHIAZOL-2-YL)METHYL]AMINO}CARBONYL)PHENOXY]ACETIC ACID, ... (4 entities in total)
• Functional Keywords: aldose reductase, ternary complex, inhibitor binding, oxidoreductase
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P15121
• Total number of polymer chains: 1
• Total formula weight: 37056.08

Authors

Ruiz, F.,Hazemann, I.,Mitschler, A.,Chevrier, B.,Schneider, T.,Joachimiak, A.,Karplus, M.,Podjarny, A. (deposition date: 2004-04-28, release date: 2004-08-03, Last modification date: 2024-03-13)

Primary citation

Ruiz, F.,Hazemann, I.,Mitschler, A.,Joachimiak, A.,Schneider, T.,Karplus, M.,Podjarny, A.
The crystallographic structure of the aldose reductase-IDD552 complex shows direct proton donation from tyrosine 48.
Acta Crystallogr.,Sect.D, 60:1347-1354, 2004

PubMed Abstract: The X-ray crystal structure of human aldose reductase (ALR2) in complex with the inhibitor IDD552 was determined using crystals obtained from two crystallization conditions with different pH values (pH 5 and 8). In both structures the charged carboxylic head of the inhibitor binds to the active site, making hydrogen-bond interactions with His110 and Tyr48 and electrostatic interactions with NADP+. There is an important difference between the two structures: the observation of a double conformation of the carboxylic acid moiety of the inhibitor at pH 8, with one water molecule interacting with the main configuration. This is the first time that a water molecule has been observed deep inside the ALR2 active site. Furthermore, in the configuration with the lower occupancy factor the difference electron-density map shows a clear peak (2.5sigma) for the H atom in the hydrogen bond between the inhibitor's carboxylic acid and the Tyr48 side-chain O atom. The position of this peak implies that this H atom is shared between both O atoms, indicating possible direct proton transfer from this residue to the inhibitor. This fact agrees with the model of the catalytic mechanism, in which the proton is donated by the Tyr48 hydroxyl to the substrate. These observations are useful both in drug design and in understanding the ALR2 mechanism.

PubMed: 15272156
DOI: 10.1107/S0907444904011370

Experimental method

X-RAY DIFFRACTION (1.8 Å)