2012
DOI: 10.1038/nsmb.2456
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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 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 lym… Show more

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Cited by 167 publications
(214 citation statements)
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“…1A). Residues comprising the GR DBD's dimerization loop, such as Ala458, Gly459, and Arg460, showed significant chemical shift perturbations when bound to (+)GRE DNA but not nGRE DNA, supporting the notion that the GR DBD binds to the TSLP nGRE as two monomers (14). Additionally, NMR peaks for arginine side chains appeared when the DBD was bound to nGRE, indicating altered rates of exchange of DBD-(+)GRE and DBD-nGRE complexes.…”
Section: Resultsmentioning
confidence: 56%
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“…1A). Residues comprising the GR DBD's dimerization loop, such as Ala458, Gly459, and Arg460, showed significant chemical shift perturbations when bound to (+)GRE DNA but not nGRE DNA, supporting the notion that the GR DBD binds to the TSLP nGRE as two monomers (14). Additionally, NMR peaks for arginine side chains appeared when the DBD was bound to nGRE, indicating altered rates of exchange of DBD-(+)GRE and DBD-nGRE complexes.…”
Section: Resultsmentioning
confidence: 56%
“…S1) indicate that DBD conformation differs when bound to distinct response elements, and such allosteric changes have been shown to affect transcriptional output (21,25). Molecular dynamics (MD) trajectories followed by community and suboptimal path analysis of the SR-DNA complexes show that AncSR2's daughter proteins in the GR and MR lineage contain more complex community organizations, resulting in diverging allosteric communication upon DNA binding among AncSR2-derived paralogs: at nGREs, the community connecting DBD monomers is much larger in hGR versus AncSR2, indicating that DNA-mediated intermonomer communication and resulting negative cooperativity at nGREs (14) is enhanced in hGR compared with AncSR2 (Fig. 3 C-F).…”
Section: Dbd-ngre Binding and Subsequent Repression Is A Feature Of Thementioning
confidence: 99%
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