NUCLEAR receptors regulate the transcription of complex networks of genes and thereby control diverse aspects of growth, development, and homeostasis. The nuclear receptor superfamily includes intracellular receptors for steroid hormones, thyroid hormones, and retinoids, as well as a large number of related proteins for which regulatory ligands have not been identified. Regardless of whether transcriptional activity is controlled by the binding of a ligand, each of these proteins must be capable of binding to specific DNA sequences that identify particular genes as targets for regulation. Elucidation of the mechanisms that underlie gene-specific recognition therefore forms a central problem in understanding how various members of the nuclear receptor superfamily function to differentially regulate gene expression.

The sequence-specific DNA binding properties of nuclear receptors are determined by two conserved domains that function in an interdependent manner to mediate protein-DNA and protein-protein interactions (Fig. 1). Protein-DNA interactions are mediated by the highly conserved DNA binding domain (DBD) that defines the nuclear receptor superfamily.