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.
