Conformational flexibility in crystal structures of human 11beta-hydroxysteroid dehydrogenase type I provide insights into glucocorticoid interconversion and enzyme regulation

Human 11beta-hydroxysteroid dehydrogenase type I (11beta-HSD1) is an ER-localized membrane protein that catalyzes the interconversion of cortisone and cortisol. In adipose tissue, excessive cortisol production through 11beta-HSD1 activity has been implicated in the pathogenesis of type II diabetes a...

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Bibliographic Details
Published in:The Journal of biological chemistry 2005-02, Vol.280 (6), p.4639
Main Authors: Hosfield, David J, Wu, Yiqin, Skene, Robert J, Hilgers, Mark, Jennings, Andy, Snell, Gyorgy P, Aertgeerts, Kathleen
Format: Article
Language:English
Subjects:
11-beta-Hydroxysteroid Dehydrogenases - chemistry
Amino Acid Motifs
Binding Sites
Cloning, Molecular
Cortisone - chemistry
Crystallography, X-Ray
Cysteine - chemistry
Diabetes Mellitus, Type 2 - metabolism
Dimerization
Disulfides - chemistry
Endoplasmic Reticulum - metabolism
Enzyme Inhibitors - pharmacology
Escherichia coli - metabolism
Glucocorticoids - chemistry
Humans
Hydrocortisone - chemistry
Kinetics
Mass Spectrometry
Models, Molecular
Mutagenesis
Obesity - metabolism
Oxygen - metabolism
Point Mutation
Proline - chemistry
Protein Binding
Protein Conformation
Protein Structure, Tertiary
Recombinant Proteins - chemistry
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Summary:Human 11beta-hydroxysteroid dehydrogenase type I (11beta-HSD1) is an ER-localized membrane protein that catalyzes the interconversion of cortisone and cortisol. In adipose tissue, excessive cortisol production through 11beta-HSD1 activity has been implicated in the pathogenesis of type II diabetes and obesity. We report here biophysical, kinetic, mutagenesis, and structural data on two ternary complexes of 11beta-HSD1. The combined results reveal flexible active site interactions relevant to glucocorticoid recognition and demonstrate how four 11beta-HSD1 C termini converge to form an as yet uncharacterized tetramerization motif. A C-terminal Pro-Cys motif is localized at the center of the tetramer and forms reversible enzyme disulfides that alter enzyme activity. Conformational flexibility at the tetramerization interface is coupled to structural changes at the enzyme active site suggesting how the central Pro-Cys motif may regulate enzyme activity. Together, the crystallographic and biophysical data provide a structural framework for understanding 11beta-HSD1 activities and will ultimately facilitate the development of specific inhibitors.
ISSN:0021-9258