Decoding DNA signals that instruct glucocorticoid receptor structure and function

The glucocorticoid receptor (GR) binds to genomic response elements and regulates gene transcription with exquisite cell- and gene-specificity. Within a response element, the precise sequence to which GR binds has been implicated in directing receptor structure and activity. Here, we use NMR to show that different binding sequences affect the conformation of distinct regions of the GR DNA binding domain. Chemical shift difference mapping and analysis of a GR mutant suggest that an allosteric pathway links the DNA-binding surface, the dimerization interface and the associated dimer partner. We show that disrupting this pathway alters sequence-specific conformations, DNA-binding kinetics and gene-specific transcriptional activity. Our study provides insight into mechanisms by which binding sequences may impart multiple activities to a single factor through gene-specific structural changes