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J. Biol. Chem., Vol. 279, Issue 48, 50050-50059, November 26, 2004

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Glucocorticoid Ligands Specify Different Interactions with NF-B by Allosteric Effects on the Glucocorticoid Receptor DNA Binding Domain^*

Helen Garside, Adam Stevens, Stuart Farrow, Claire Normand¶, Benoit Houle||, Andy Berry, Barbara Maschera, and David Ray**

From the Centre for Molecular Medicine and Endocrine Sciences Research Group, Stopford Building, Faculty of Medicine, University of Manchester, Oxford Road, Manchester M13 9PT, United Kingdom, the Department of Asthma Biology, GlaxoSmithKline, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, United Kingdom, ^¶PerkinElmer Life & Analytical Sciences, PerkinElmer BioSignal Inc., Montreal, Quebec H3J 1R4, Canada, and the ^||Montreal Proteomics Network, Montreal, Quebec H3A 1A4, Canada

Glucocorticoids inhibit inflammation by acting through the glucocorticoid receptor (GR) and powerfully repressing NF-B function. Ligand binding to the C-terminal of GR promotes the nuclear translocation of the receptor and binding to NF-B through the GR DNA binding domain. We sought how ligand recognition influences the interaction between NF-B and GR. Both dexamethasone (agonist) and RU486 (antagonist) promote efficient nuclear translocation, and we show occupancy of the same intranuclear compartment as NF-B with both ligands. However, unlike dexamethasone, RU486 had negligible activity to inhibit NF-B transactivation. This failure may stem from altered co-factor recruitment or altered interaction with NF-B. Using both glutathione S-transferase pull-down and bioluminescence resonance energy transfer approaches, we identified a major glucocorticoid ligand effect on interaction between the GR and the p65 component of NF-B, with RU486 inhibiting recruitment compared with dexamethasone. Using the bioluminescence resonance energy transfer assay, we found that RU486 efficiently recruited NCoR to the GR, unlike dexamethasone, which recruited SRC1. Therefore, RU486 promotes differential protein recruitment to both the C-terminal and DNA binding domain of the receptor. Importantly, using chromatin immunoprecipitation, we show that impaired interaction between GR and p65 with RU486 leads to reduced recruitment of the GR to the NF-B-responsive region of the interleukin-8 promoter, again in contrast to dexamethasone that significantly increased GR binding. We demonstrate that ligand-induced conformation of the GR C-terminal has profound effects on the functional surface generated by the DNA binding domain of the GR. This has implications for understanding ligand-dependent interdomain communication.

Received for publication, June 30, 2004 , and in revised form, September 7, 2004.

^* This work was supported by the Biotechnology and Biological Sciences Research Council and GlaxoSmithKline. 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.

^** Supported by a GlaxoSmithKline fellowship. To whom correspondence should be addressed. Tel.: 44-161-275-5655; Fax: 44-161-275-5958; E-mail: david.w.ray{at}man.ac.uk.

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