Abstract

Steroid hormone receptors are members of a superfamily of ligand-dependent transcription factors. As such they have a DNA binding domain that recognizes specific target gene sequences along with separate transcriptional activation domains. What sets steroid hormone receptors (and other nuclear hormone receptors) apart from other families of sequence specific transcriptional activators is the presence of a ligand binding domain (LBD) that acts as a molecular switch to turn on transcriptional activity when a hormonal ligand induces a conformational change in the receptor. Upon binding hormone, steroid receptors recruit a novel coactivator protein complex with an essential role in receptor-mediated transcriptional activation. Coactivators function as adaptors in a signaling pathway that transmits transcriptional responses from the DNA bound receptor to the basal transcriptional machinery. Hormone agonists induce a conformational change in the carboxyl-terminal transcriptional activation domain, AF-2, that creates a new protein interaction site on the surface of the LBD that is recognized by LXXLL motifs in the p160 family of coactivators. In contrast, steroid antagonists such as the antiestrogen tamoxifen for the estrogen receptor induce an alternate conformation in AF-2 that occludes the coactivator binding site and recruits corepressors that can actively silence steroid responsive genes. Thus, the cellular availability of coactivators and corepressors is an important determinant in the biological response to both steroid hormone agonists and antagonists. This paper provides an update on the properties and mechanism of action of nuclear receptor coactivators, the nature of the coactivator-binding site, and the structural and mechanistic basis for ligand-dependent binding of coactivators to receptors.