A Vitamin D Receptor Selectively Activated by Gemini Analogs Reveals Ligand Dependent and Independent Effects

作者：Huet Tiphaine; Laverny Gilles; Ciesielski Fabrice; Molnar Ferdinand; Ramamoorthy Thanuja Gali; Belorusova Anna Y; Antony Pierre; Potier Noelle; Metzger Daniel^*; Moras Dino; Rochel Natacha

来源：Cell Reports, 2015, 10(4): 516-526.

DOI：10.1016/j.celrep.2014.12.045

The bioactive form of vitamin D [1,25(OH)(2)D-3] regulates mineral and bone homeostasis and exerts potent anti-inflammatory and antiproliferative properties through binding to the vitamin D receptor (VDR). The 3D structures of the VDR ligand-binding domain with 1,25(OH)(2)D-3 or gemini analogs unveiled the molecular mechanism underlying ligand recognition. On the basis of structure-function correlations, we generated a point-mutated VDR (VDRgem) that is unresponsive to 1,25(OH)(2)D-3, but the activity of which is efficiently induced by the gemini ligands. Moreover, we show that many VDR target genes are repressed by unliganded VDRgem and that mineral ion and bone homeostasis are more impaired in VDRgem mice than in VDR null mice, demonstrating that mutations abolishing VDR ligand binding result in more severe skeletal defects than VDR null mutations. As gemini ligands induce VDRgem transcriptional activity in mice and normalize their serum calcium levels, VDRgem is a powerful tool to further unravel both liganded and unliganded VDR signaling.

• 出版日期2015-2-3