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  • Title: 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.
    Author: Thompson PD, Jurutka PW, Haussler CA, Whitfield GK, Haussler MR.
    Journal: J Biol Chem; 1998 Apr 03; 273(14):8483-91. PubMed ID: 9525962.
    Abstract:
    Gel mobility shift analysis was utilized to investigate the molecular function of 1alpha,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 as 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 RXR, 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 allosteric switch in VDR to a form that not only binds to the VDRE with high affinity and specificity as a heterodimer with RXR, but also interacts with the RXR partner to conformationally restrict the action of its cognate ligand.
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