Regulation of the vitamin D receptor by vitamin D lactam derivatives.

The active metabolite of vitamin D3, 1α,25-dihydroxyvitamin D3, acts as a ligand for the vitamin D receptor ( VDR) and activates VDR-mediated gene expression. Recently, we characterized 1α,25-dihydroxyvitamin D3-26,23-lactams ( DLAMs), which mimic vitamin D3 metabolites, as noncalcemic VDR ligands that barely activate the receptor. In this study, we present structural insights onto the regulation of VDR function by DLAMs. X-ray crystallographic analysis revealed that DLAMs induced a large conformational change in the loop region between helices H6 and H7 in the VDR ligand-binding domain. Our structural analysis suggests that targeting of the loop region may be a new mode of VDR regulation. [ABSTRACT FROM AUTHOR]