The vitamin D3 receptor (VDR), which is the nuclear receptor for 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3], acts primarily as a heterodimer with the retinoid X receptor (RXR) and binds preferentially to directly repeated arrangements of two hexameric binding sites with three spacing nucleotides [DR3-type vitamin D response elements (VDREs)]. In this study, all presently known natural DR3-type VDREs have been compared and classified on the basis of their complex-formation with VDR–RXR heterodimers and their ability to stabilize VDR–RXR heterodimer conformations. Based on the affinity of each VDRE for VDR–RXR heterodimers, the DR3-type VDREs were divided into three classes. The ligand sensitivity of this complex-formation and conformational stabilization was determined to be in the range of 0.1nM. No significant differences in the 1α,25(OH)2D3-modulated interactions of the DR3-type VDRE-complexed VDR–RXR heterodimer with the co-activator SRC-1 (steroid receptor co-activator-1) or the co-repressor NCoR (nuclear receptor co-repressor) were found. Taken together, the affinity for VDR–RXR heterodimers appears to be the major discriminating parameter between natural DR3-type VDREs. This will not only facilitate further investigation of the principles of DR3-type-VDRE-mediated gene regulation, but also strongly suggests that DR3-type VDREs alone cannot explain the pleiotropic genomic action of 1α,25(OH)2D3.

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