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Science 324 (5925): 407-410

Copyright © 2009 by the American Association for the Advancement of Science

DNA Binding Site Sequence Directs Glucocorticoid Receptor Structure and Activity

Sebastiaan H. Meijsing,1* Miles A. Pufall,1* Alex Y. So,1,2 Darren L. Bates,3 Lin Chen,3 Keith R. Yamamoto1,2{dagger}

Abstract: Genes are not simply turned on or off, but instead their expression is fine-tuned to meet the needs of a cell. How genes are modulated so precisely is not well understood. The glucocorticoid receptor (GR) regulates target genes by associating with specific DNA binding sites, the sequences of which differ between genes. Traditionally, these binding sites have been viewed only as docking sites. Using structural, biochemical, and cell-based assays, we show that GR binding sequences, differing by as little as a single base pair, differentially affect GR conformation and regulatory activity. We therefore propose that DNA is a sequence-specific allosteric ligand of GR that tailors the activity of the receptor toward specific target genes.

1 Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94158, USA.
2 Chemistry and Chemical Biology Program, University of California, San Francisco, CA 94107, USA.
3 Department of Molecular and Computational Biology, University of Southern California, Los Angeles, CA 90089, USA.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: yamamoto{at}cmp.ucsf.edu


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