Structural elements of an orphan nuclear receptor-DNA complex

The nuclear hormone receptors form the largest known family of transcription factors. The current notion of receptor DNA discrimination, based solely on one major type of hexameric half-site and a highly conserved be-residue core DNA-binding domain (DBD), does not adequately describe how more than 150 nonsteroid receptors differentiate among response elements. Here, we describe the 2.3 Angstrom crystal structure of the DNA-binding region of the orphan receptor RevErb arranged as a tandem homodimer on its optimal response element. The structure reveals the presence of a second major protein-DNA interface adjacent to the classical one involving the half-sites. A sequence comparison of orphan receptors suggests that unique minor-groove interactions involving the receptor hinge regions impart the necessary DNA and dimerization specificity.