Vitamin D Receptor-DNA Interactions

The vitamin D receptor (VDR) is a member of the steroid and nuclear hormone receptor superfamily of eukaryotic transcription factors and binds target DNA, or response elements, as a homodimer or heterodimer with the 9-cis retinoid X receptor (RXR). In this chapter, we survey the current understanding of VDR-DNA interactions, emphasizing recent structural insights. We highlight the stereochemical interactions that dictate DNA binding and hexameric half-site sequence affinity as well as the protein-protein interactions that account for preferential binding to a direct repeat of half-sites with three base pairs of spacer DNA (DR3). In addition, we review alternative response element arrangements other than those with DR3. Finally, the chapter discusses the VDR DNA binding domain (DBD) and suggests that it violates classical canons because it does not heterodimerize with the RXR DBD. This unique behavior of VDR is considered in light of recent results demonstrating the formation of VDR DBD-DNA and DR3 DBD-DNA complexes with RXR using a mutant VDR protomer.