Ranvir Singh and Mark A. White contributed equally to this paper.
Structure of a glutathione conjugate bound to the active site of aldose reductase†
Article first published online: 25 APR 2006
Copyright © 2006 Wiley-Liss, Inc.
Proteins: Structure, Function, and Bioinformatics
Volume 64, Issue 1, pages 101–110, 1 July 2006
How to Cite
Singh, R., White, M. A., Ramana, K. V., Petrash, J. M., Watowich, S. J., Bhatnagar, A. and Srivastava, S. K. (2006), Structure of a glutathione conjugate bound to the active site of aldose reductase. Proteins, 64: 101–110. doi: 10.1002/prot.20988
The Atomic coordinates and structure factors (code 2F2K) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org).
- Issue published online: 12 MAY 2006
- Article first published online: 25 APR 2006
- Manuscript Revised: 7 FEB 2006
- Manuscript Received: 23 AUG 2005
- Manuscript Accepted: 20 FEB 2005
- NIH. Grant Numbers: DK36118, EY01677, GM71036, HL59378
- Sealy and Smith Foundation
- Sealy Center for Structural Biology. Grant Number: NIEHS ESO6676–11
- aldo–keto reductase;
- competitive inhibitor;
- active site;
- diabetic complications;
- crystal structure;
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 Å. 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. Proteins 2006. © 2006 Wiley-Liss, Inc.