Abstract
The vitamin D receptor (VDR), the high affinity receptor for 1α,25-dihydroxyvitamin D3 (1a,25(OH)2D3), is a member of the nuclear receptor superfamily. VDR preferentially forms a heterodimeric complex with the retinoid Xreceptor (RXR) and binds to 1a,25(OH)2D3response 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 ofnuclear 1a,25(OH)2D3signaling by transmitting its activation status to differentchromatin loci containing the 1a,25(OH)2D3target genes. Approximately0.5% of the human genome (about 200 genes) are estimated to be primary targets of 1α,25(OH)2D3, but via various mechanisms the VDR appears to interferein the regulation of even more genes. The molecular basis of the regulatoryactions of 1α,25(OH)2D3and its synthetic analogs are ligand-triggered proteinprotein interactions of the ligand-binding domain (LBD) of the VDRwith coactivator (CoA), corepressor (CoR) and other nuclear proteins. Mostanalogs 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.
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Carlberg, C. (2003). Current Understanding of the Function of the Nuclear Vitamin D Receptor in Response to Its Natural and Synthetic Ligands. In: Reichrath, J., Tilgen, W., Friedrich, M. (eds) Vitamin D Analogs in Cancer Prevention and Therapy. Recent Results in Cancer Research, vol 164. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-55580-0_2
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DOI: https://doi.org/10.1007/978-3-642-55580-0_2
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