Glucocorticoid receptor signaling: intricacies and therapeutic opportunities.

By integrating technologies that study chromatin conformation, accessibility, modification, and coregulator recruitment, the molecular basis of the cell-type-specific actions of glucocorticoids (GCs) can be increasingly understood. Therapeutic exploitation of crosstalk between nuclear receptors is gaining traction and has offered strategies to sensitize cells to GCs. Conformational analyses of the glucocorticoid receptor (GR) [via hydrogen–deuterium exchange mass spectrometry (HDX-MS)] are offering a biophysical basis for ligand-binding domain (LBD)–DNA-binding domain (DBD) interdomain communication, the degree of which differs depending on the ligand. Chromatin remodeling complexes are essential to finetune GR activity, not only for transcriptional activation but also for transcriptional repression. Condensate formation is emerging as an important determinant of GR complex assembly on chromatin. The glucocorticoid receptor (GR) is a major nuclear receptor (NR) drug target for the treatment of inflammatory disorders and several cancers. Despite the effectiveness of GR ligands, their systemic action triggers a plethora of side effects, limiting long-term use. Here, we discuss new concepts of and insights into GR mechanisms of action to assist in the identification of routes toward enhanced therapeutic benefits. We zoom in on the communication between different GR domains and how this is influenced by different ligands. We detail findings on the interaction between GR and chromatin, and highlight how condensate formation and coregulator confinement can perturb GR transcriptional responses. Last, we discuss the potential of novel ligands and the therapeutic exploitation of crosstalk with other NRs. [ABSTRACT FROM AUTHOR]