Variable steroid receptor responses: Intrinsically disordered AF1 is the key

[Display omitted] •Control of steroid hormone specifity in regulation of gene expression.•Cofactor-induced changes in receptor structure.•Alteration of remote regions of receptor structure by steroidal ligand.•Modulation of ligand potency and efficacy by changing cofactor concentration. Steroid hormones, acting through their cognate receptor proteins, see widespread clinical applications due to their ability to alter the induction or repression of numerous genes. However, steroid usage is limited by the current inability to control off-target, or non-specific, side-effects. Recent results from three separate areas of research with glucocorticoid and other steroid receptors (cofactor-induced changes in receptor structure, the ability of ligands to alter remote regions of receptor structure, and how cofactor concentration affects both ligand potency and efficacy) indicate that a key element of receptor activity is the intrinsically disordered amino-terminal domain. These results are combined to construct a novel framework within which to logically pursue various approaches that could afford increased selectivity in steroid-based therapies.