A structural view of ligand binding to the retinoid receptors

Nuclear receptors play an important role in transcription regulation. They bind as homoor heterodimers to the response elements of their target genes and interact with numerous and diverse partners, e. g. coactivator and corepressor proteins, and transcription factors. Many of these processes are ligand-dependent, i. e. binding of natural ligands activates the nuclear receptor through conformational changes of the protein. Synthetic ligands can be made specific for a particular receptor and have the potential for reducing the side-effects of natural ligands in pharmaceutical applications. The crystal structures of ligand-binding domains of the retinoid receptors have brought the first insight into the spatial organization and the nature of the ligand-induced changes at the atomic level. Furthermore, these structures provide a starting point for structure-based drug design of retinoids. The nuclear receptor superfamilv Cells use two principal pathways to transmit signals from the exterior through the cytoplasm to the nucleus. In the first one, membrane receptors bind ligands at the cell surface which do not cross the membrane themselves. For example, after the binding of growth factors to membrane receptors the signal is transmitted by a cascade involving serineor tyrosine-kinases. The receptors for EGF (epidermal growth factor) and NGF (nerve growth factor) utilize water-soluble ligands such as peptide hormones and growth factors, where the mitogenic action of EGF is mediated by ligand-induced autophosphorylation of the EGF receptor. The polypeptidic neurotrophins promote differentiation and survival of peripheral and central neurons. In the second pathway, the intracellular nuclear receptors control the activity of their target genes directly by binding to specific DNA-sequences called hormone response elements. Unlike membrane-bound receptors, nuclear receptors bind lipophilic hormones, which can cross the lipid bilayer of the cell membrane and then bind to their cognate receptors, either in the cytoplasm or the nucleus. These include receptors for steroidhormones (ER, estrogen receptor, GR, glucocorticoid receptor, among others), vitamin D (VDR), thyroid hormone (TR) and retinoids (RAR and RXR), which are vitamin A metabolites. Not all these ligands are exclusively endocrine. Some of thern need to be metabolically modified, as retinoic acid, others are completely synthesized in the cell, as prostaglandins. All these receptors are ligand-inducible transcription regulators, and are involved in development and cell differentiation (reviewed in refs. 1 and 2). Additionally, the so-called orphan receptors either are constitutively active or their ligands are not yet known. It is interesting to note that the nuclear and membrane receptor pathways are connected, as for example retinoic acid (RA) and EGF (refs. 3 and 4), and RA and NGF (ref. 5) , respectively, show cooperative effects on cell growth via RARs/RXRs.