The nuclear receptor superfamily.

Nuclear receptors are one of the most abundant classes of transcriptional regulators in animals (metazoans). They regulate diverse functions, such as homeostasis, reproduction, development and metabolism (for a review, see Laudet and Gronemeyer, 2002). Nuclear hormone receptors function as ligandactivated transcription factors, and thus provide a direct link between signaling molecules that control these processes and transcriptional responses. A large number of nuclear receptors have been identified through sequence similarity to known receptors, but have no identified natural ligand, and are referred to as ‘nuclear orphan receptors’. As nuclear receptors bind small molecules that can easily be modified by drug design, and control functions associated with major diseases (e.g. cancer, osteoporosis and diabetes), they are promising pharmacological targets. The search for ligands for orphan receptors and the identification of novel signaling pathways has become a very active research field (Gustafsson, 1999; Kliewer et al., 1999). Canonical structure Nuclear receptors share a common structural organization. The N-terminal region (A/B domain) is highly variable, and contains at least one constitutionally active transactivation region (AF-1) and several autonomous transactivation domains (AD); A/B domains are variable in length, from less than 50 to more than 500 amino acids, and their 3D structure is not known. The most conserved region is the DNA-binding domain (DBD, C domain), which notably contains the P-box, a short motif responsible for DNA-binding specificity on sequences typically containing the AGGTCA motif, and is involved in dimerization of nuclear receptors. This dimerization includes homodimers as well as heterodimers. The 3D structure of the DBD has been resolved for a number of nuclear receptors and Cell Science at a Glance 585