Structural Elements of an Orphan Nuclear Receptor–DNA Complex

Abstract

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 66-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 Å 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.