Structure function relationships of VDR ligands

Most of the biological actions of 1α,25-dihydroxyvitamin D3 (1,25[OH]2D3) are mediated via the vitamin D receptor (VDR). More than 3000 VDR ligands have been developed, with the goal to improve the biological profile of 1,25(OH)2D3 for therapeutic applications in either bone disorders or hyperproliferative diseases. Crystal structures of the VDR ligand-binding domain complexed with agonistic, partial agonistic, and antagonistic ligands exhibit almost identical active conformations; thus, these crystal structures cannot fully explain the mechanisms underlying differences in biological activity. Recent studies of VDR/ligand complexes in solution using modern techniques such as hydrogen-deuterium exchange coupled with mass spectrometry (HDX-MS) and small-angle X-ray scattering coupled with molecular dynamics (SAXS-MD) have provided a somewhat more-comprehensive perspective of agonism, partial agonism, and antagonism. This chapter discusses the molecular mechanisms of these different types of analogs based on crystal structure, HDX-MS, and SAXS-MD analyses.