The structure of the nuclear hormone receptors

The functions of the group of proteins known as nuclear receptors will be u nderstood fully only when their working three-dimensional structures are kn own. These ligand-activated transcription factors belong to the steroid-thy roid-retinoid receptor superfamily, which include the receptors for steroid s, thyroid hormone, vitamins A- and D-derived hormones, and certain fatty a cids. The majority of family members are homologous proteins for which no l igand has been identified (the orphan receptors). Molecular cloning and str ucture/function analyses have revealed that the members of the superfamily have a common functional domain structure. This includes a variable N-termi nal domain, often important for transactivation of transcription; a well co nserved DNA-binding domain, crucial for recognition of specific DNA sequenc es and protein:protein interactions; and at the C-terminal end, a ligand-bi nding domain, important for hormone binding, protein: protein interactions, and additional transactivation activity. Although the structure of some in dependently expressed single domains of a few of these receptors have been solved, no holoreceptor structure or structure of any two domains together is yet available. Thus, the three-dimensional structure of the DNA-binding domains of the glucocorticoid, estrogen, retinoic acid-beta, and retinoid X receptors, and of the ligand-binding domains of the thyroid, retinoic acid -gamma, retinoid X, estrogen, progesterone, and peroxisome proliferator act ivated-gamma receptors have been solved. The secondary structure of the glu cocorticoid receptor N-terminal domain, in particular the tau1 transcriptio n activation region, has also been studied. The structural studies availabl e not only provide a beginning stereochemical knowledge of these receptors, but also a basis for understanding some of the topological details of the interaction of the receptor complexes with coactivators, corepressors, and other components of the transcriptional machinery. In this review, we summa rize and discuss the current information on structures of the steroid-thyro id-retinoid receptors. (C) 1999 Elsevier Science Inc. All rights reserved.