Structure and Inhibitor Binding Mechanisms of 11β -Hydroxysteroid Dehydrogenase Type 1

Author(s): Zhulun Wang, Minghan Wang.

Journal Name: Current Chemical Biology

Volume 3 , Issue 2 , 2009

Become EABM
Become Reviewer

Abstract:

11β-Hydroxysteroid dehydrogenase (11β-HSD1) is involved in glucocorticoid activation in a tissue-specific manner. In tissues and intact cells, it functions primarily as a reductase by converting inactive cortisone to cortisol. Since glucocorticoid action is implicated in the development of the metabolic syndrome, inhibition of 11β-HSD1 has been proposed as a therapeutic strategy to treat type 2 diabetes. 11β-HSD1 is a member of the short chain dehydrogenase/reductase (SDR) superfamily with the “Y183SASK187” sequence and Ser170 at the active site that matches the catalytic domain signature motif of “YXXXK” in SDRs. The recent success in the determination of various 11β-HSD1 3-dimentional structures has facilitated a higher level understanding of the interactions among the enzyme, the cofactor and the substrate as well as substrate site inhibitors. In particular, the structural analysis of 11β-HSD1 in complex with a non-selective inhibitor carbenoxolone (CBX) has advanced our knowledge of inhibitor-enzyme interactions. In addition to the catalytic triad, residues close to the steroid binding site and surrounding areas have been identified as important in stabilizing the substrate. These findings have accelerated medicinal chemistry efforts to discover selective 11β-HSD1 inhibitors in the pharmaceutical industry. A large number of chemical classes have been identified as potent and selective 11β-HSD1 inhibitors. Some common features in enzyme-inhibitor interactions were observed with structurally distinct compounds. Chemical class-specific interactions were discovered as well, which explain the structural diversity of selective 11β-HSD1 inhibitors. In this article, we review the structural characteristics of 11β-HSD1 enzymes in several species. By comparing active sites, substrate binding and subunit interactions, we have identified structural features and residues in the active site important for inhibitor binding. Further, through analysis of the major interactions between the active site residues and inhibitors of different chemical classes, we have determined compound class-specific structural requirements for optimal enzyme- inhibitor interaction.

Keywords: 11β-hydroxysteroid dehydrogenase, inhibitor binding, cortisol, CBX, active site, dimer partner, co-crystal structure

Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 3
ISSUE: 2
Year: 2009
Page: [159 - 170]
Pages: 12
DOI: 10.2174/2212796810903020159
Price: $58

Article Metrics

PDF: 6