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The structural basis of direct glucocorticoid-mediated transrepression

Abstract

A newly discovered negative glucocorticoid response element (nGRE) mediates DNA-dependent transrepression by the glucocorticoid receptor (GR) across the genome and has 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 GR, we characterized the interaction between GR and an nGRE in the thymic stromal lymphopoietin (TSLP) promoter. We show using structural and mechanistic approaches that nGRE binding is 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.

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Figure 1: GR interacts with nGREs in a unique orientation, preventing receptor dimerization.
Figure 2: GR uses unique interactions to recognize the high-affinity site within nGREs.
Figure 3: The GR R460D D462R mutant reduces receptor dimerization, enhancing GR-mediated transrepression at the TSLP nGRE.

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Acknowledgements

We thank N.M. Choi, O. Laur and members of the Emory Custom Cloning Core Facility for assistance with cloning the TSLP-nGRE reporter construct. This work was supported with start-up funds from Emory University. W.H.H. was supported by an Emory–National Institute of Health Pharmacological Sciences graduate training grant (5T32GM008602).

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W.H.H. and E.A.O. designed the experiments, W.H.H. and C.Y. performed the experiments, and W.H.H. and E.A.O. wrote the manuscript.

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Correspondence to Eric A Ortlund.

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Hudson, W., Youn, C. & Ortlund, E. The structural basis of direct glucocorticoid-mediated transrepression. Nat Struct Mol Biol 20, 53–58 (2013). https://doi.org/10.1038/nsmb.2456

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