The structural basis of direct glucocorticoid-mediated transrepression

• Authors: William H. Hudson, Emory University; Christine Youn, Emory University; Eric Ortlund, Emory University
• Journal Title: Nature Structural and Molecular Biology
• Volume: Volume 20, Number 1
• Publisher: Nature Research (part of Springer Nature) | 2013-01, Pages 53-58
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1038/nsmb.2456
• Subjects: Health Sciences, General; Chemistry, Biochemistry

Abstract

A newly discovered negative glucocorticoid response element (nGRE) mediates DNA-dependent transrepression by the glucocorticoid receptor (GR) across the genome and plays a major role in immunosuppressive therapy. The nGRE differs dramatically from activating response elements and the mechanism driving GR binding and transrepression is unknown. To unravel the mechanism of nGRE-mediated transrepression by the glucocorticoid receptor, we characterize the interaction between GR and a nGRE in the thymic stromal lymphopoetin (TSLP) promoter. We show using structural and mechanistic approaches that nGRE binding represents a new mode of sequence recognition by human GR and that nGREs prevent receptor dimerization through a unique GR-binding orientation and strong negative cooperativity, ensuring the presence of monomeric GR at repressive elements.