Structural determinants of DNA-binding specificity by steroid receptors.

Specific DNA binding by transcription factors constitutes an important part of the specificity of gene regulation. Many transcription factors are members of large families of proteins that bind to similar, but distinct, DNA sequences. The individual proteins must be able to distinguish between the closely related DNA sequences. The nuclear receptors form a family of transcription factors that are activated by steroid hormones, thyroid hormone, retinoids, and vitamin D, (for reviews see Refs. l-3). Many orphan nuclear receptors have been identified for which no ligands have been found as yet. Upon ligand binding the receptors interact with specific DNA sequences near the regulated gene, called response elements, and activate or repress gene transcription. The members of the nuclear receptor family regulate different aspects of development, differentiation, growth, homeostasis, and metabolism in the cell. The specific functions of the members of the family depend upon the genes that they regulate. Part of the specificity of gene regulation within the family is due to the recognition of the response elements with which the nuclear receptors interact. The response elements are composed of 6 base pair half-site sequences that are organized as palindromic or direct repeats. The nuclear receptors bind mainly as dimers to the response element, and each monomer interacts with a half-site sequence within the response element. The nuclear receptors can be divided into two classes depending upon their DNA recognition. Most members of the nuclear receptor family, including the estrogen receptor (ER), recognize the same DNA half-site sequence, and the specificity within this group is determined by recognition of different organizations of the half-sites. The glucocorticoid receptor (GR) group, which also in-