Heterodimeric DNA binding by the vitamin D receptor and retinoid X receptors is enhanced by 1,25-dihydroxyvitamin D₃ and inhibited by 9-cis- retinoic acid. Evidence for allosteric receptor interactions

Gel mobility shift analysis was utilized to investigate the molecular function of 1α,25-dihydroxyvitamin D₃ (1,25-(OH)₂D₃) and 9-cis-retinoic acid (9-cis-RA) ligands in the binding of the vitamin D receptor (VDR) and retinoid X receptor (RXR) to mouse osteopontin and rat osteocalcin vitamin D- response elements (VDREs). At physiological ionic strength and reduced concentrations of expressed proteins, efficient binding to either VDRE occurs as a VDR·RXR heterodimer, not ms a VDR homodimer. 1,25-(OH)₂D₃ dramatically enhances heterodimer-VDRE interaction, whereas somewhat higher concentrations of 9-cis-RA inhibit this association, perhaps related to the role of this retinoid in facilitating RXR homodimer formation. Interestingly, if VDR is occupied by 1,25-(OH)₂D₃ prior to complexing with the resulting heterodimer is relatively resistant to dissociation and diversion to other pathways by 9-cis-RA. Therefore, a proposed molecular action of 1,25- (OH)₂D₃ is to generate an allosterie switch in VDR to a form that not only binds to the VDRE with affinity and specificity as a heterodimer with RXR, but also interacts with the RXR partner to conformationally restrict the action of its cognate ligand.