Nuclear vitamin D receptor: Natural ligands, molecular structure-function, and transcriptional control of vital genes

Small Angle X-ray Scattering and Fluorescence Resonance Energy Transfer techniques have determined the structure of the hypocalcemic vitamin-D-resistant rickets (hVDR) DNA-binding domain (DBD) and ligand-binding domain (LBD) together in the full-length receptor, heterodimerized with full-length RXR α, docked on a VDRE, and occupied with 1,25(OH)₂D₃ plus a single coactivator, allowing one to begin to understand the interactions between the DBD and the ligand-binding/heterodimerization domains of both VDR and its RXR heteropartner. A second major realm of accomplishment has been the identification of numerous additional VDR-regulated genes, including those mediating calcium and particularly phosphate homeostasis, bone metabolism, detoxification, cell proliferation, differentiation, migration and death, immunity and antimicrobial action, as well as carbohydrate, lipid, and amino acid metabolism. Equally exciting has been the discovery of additional natural VDR ligands, especially in the more-recently identified and studied VDR target tissues such as the hair follicle/skin and immune systems. The availability of this information will facilitate molecular investigations of transcriptional control by VDR in target-cell specific environments in the presence of novel ligands and the context of a myriad of promoters/genes. Such experiments are likely to extend the understanding of the variety of conformations and coregulator associations that the VDR-RXR heterodimer is capable of achieving while performing its multitude of extraosseous effects to lower the risk of the chronic diseases of aging.