2F2K

Aldose reductase tertiary complex with NADPH and DEG

Summary for 2F2K

• Entry DOI: 10.2210/pdb2f2k/pdb
• Related: 1ADS
• Descriptor: Aldose reductase, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, GAMMA-GLUTAMYL-S-(1,2-DICARBOXYETHYL)CYSTEINYLGLYCINE, ... (4 entities in total)
• Functional Keywords: inhibitor, glutathione, tertiary complex, dicarboxyethyl glutathione, oxidoreductase
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P15121
• Total number of polymer chains: 1
• Total formula weight: 37067.16

Authors

Singh, R.,White, M.A.,Ramana, K.V.,Petrash, J.M.,Watowich, S.J.,Bhatnagar, A.,Srivastava, S.K. (deposition date: 2005-11-17, release date: 2006-05-16, Last modification date: 2023-08-23)

Primary citation

Singh, R.,White, M.A.,Ramana, K.V.,Petrash, J.M.,Watowich, S.J.,Bhatnagar, A.,Srivastava, S.K.
Structure of a glutathione conjugate bound to the active site of aldose reductase.
Proteins, 64:101-110, 2006

PubMed Abstract: Aldose reductase (AR) is a monomeric NADPH-dependent oxidoreductase that catalyzes the reduction of aldehydes, ketones, and aldo-sugars. AR has been linked to the development of hyperglycemic injury and is a clinical target for the treatment of secondary diabetic complications. In addition to reducing glucose, AR is key regulator of cell signaling through it's reduction of aldehydes derived from lipoproteins and membrane phospholipids. AR catalyzes the reduction of glutathione conjugates of unsaturated aldehydes with higher catalytic efficiency than free aldehydes. The X-ray structure of human AR holoenzyme in complex with the glutathione analogue S-(1,2-dicarboxyethyl) glutathione (DCEG) was determined at a resolution of 1.94 A. The distal carboxylate group of DCEG's dicarboxyethyl moiety interacted with the conserved AR anion binding site residues Tyr48, His110, and Trp111. The bound DCEG's glutathione backbone adopted the low-energy Y-shape form. The C-terminal carboxylate of DCEG glutathione's glycine formed hydrogen bonds to Leu301 and Ser302, while the remaining interactions between DCEG and AR were hydrophobic, permitting significant flexibility of the AR and glutathione (GS) analogue interaction. The observed conformation and interactions of DCEG with AR were consistent with our previously published molecular dynamics model of glutathionyl-propanal binding to AR. The current structure identifies major interactions of glutathione conjugates with the AR active-site residues.

PubMed: 16639747
DOI: 10.1002/prot.20988

Experimental method

X-RAY DIFFRACTION (1.94 Å)