alexa Current understanding of the function of the nuclear vitamin D receptor in response to its natural and synthetic ligands.
Dentistry

Dentistry

JBR Journal of Interdisciplinary Medicine and Dental Science

Author(s): Carlberg C

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Abstract The vitamin D receptor (VDR), the high affinity receptor for 1alpha,25-dihydroxyvitamin D3 (1alpha,25(OH)2D3), is a member of the nuclear receptor superfamily. VDR preferentially forms a heterodimeric complex with the retinoid X receptor (RXR) and binds to 1alpha,25(OH)2D3 response elements (VDREs) that consist of two hexameric motifs in a directly repeated (DR) or inverted palindromic (IP) arrangement. DNA-complexed VDR acts as a molecular switch of nuclear 1alpha,25(OH)2D3 signaling by transmitting its activation status to different chromatin loci containing the 1alpha,25(OH)2D3 target genes. Approximately 0.5\% of the human genome (about 200 genes) are estimated to be primary targets of 1alpha,25(OH)2D3, but via various mechanisms the VDR appears to interfere in the regulation of even more genes. The molecular basis of the regulatory actions of 1alpha,25(OH)2D3 and its synthetic analogs are ligand-triggered protein-protein interactions of the ligand-binding domain (LBD) of the VDR with coactivator (CoA), corepressor (CoR) and other nuclear proteins. Most analogs have been identified as agonists, a few as antagonists (ZK159222 and TEI-9647) and only Gemini and some of its variations as nonagonists. The positioning of helix 12 of the LBD is of critical importance for the agonistic, antagonistic and nonagonistic conformation of the VDR. In each of the three conformations, the VDR performs different protein-protein interactions, which then result in a characteristic functional profile. The functional profile of some 1alpha,25(OH)2D3 analogs, such as EB1089 and Gemini, can be modulated by protein and DNA interaction partners of the VDR. This provides them with some selectivity for DNA-dependent and -independent signaling pathways and VDRE structures.
This article was published in Recent Results Cancer Res and referenced in JBR Journal of Interdisciplinary Medicine and Dental Science

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