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J. Biol. Chem., Vol. 280, Issue 6, 4639-4648, February 11, 2005

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Conformational Flexibility in Crystal Structures of Human 11-Hydroxysteroid Dehydrogenase Type I Provide Insights into Glucocorticoid Interconversion and Enzyme Regulation^*

David J. Hosfield, Yiqin Wu, Robert J. Skene, Mark Hilgers, Andy Jennings, Gyorgy P. Snell, and Kathleen Aertgeerts

From the Syrrx Inc., San Diego, California 92121

Human 11-hydroxysteroid dehydrogenase type I (11-HSD1) is an ER-localized membrane protein that catalyzes the interconversion of cortisone and cortisol. In adipose tissue, excessive cortisol production through 11-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 11-HSD1. The combined results reveal flexible active site interactions relevant to glucocorticoid recognition and demonstrate how four 11-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 11-HSD1 activities and will ultimately facilitate the development of specific inhibitors.

Received for publication, September 28, 2004 , and in revised form, October 27, 2004.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The atomic coordinates and structure factors (codes 1XU7 and 1XU9) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

To whom correspondence should be addressed: Dept. of Structural Chemistry, Syrrx Inc. 10410 Science Center Drive, San Diego, CA 92121. Tel.: 858-731-3574; E-mail: david.hosfield{at}syrrx.com.

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