Molecular basis of the selective activity of vitamin D analogues

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Abstract
More than 2,000 synthetic analogues of the biological active form of vitamin D, 1α,25‐dihydroxyvitamin D3 (1α,25(OH)2D3), are presently known. Basically, all of them interfere with the molecular switch of nuclear 1α,25(OH)2D3 signaling, which is the complex of the vitamin D receptor (VDR), the retinoid X receptor (RXR), and a 1α,25(OH)2D3 response element (VDRE). Central element of this molecular switch is the ligand‐binding domain (LBD) of the VDR, which can be stabilized by a 1α,25(OH)2D3 analogue either in its agonistic, antagonistic, or non‐agonistic conformation. The positioning of helix 12 of the LBD is of most critical importance for these conformations. In each of the three conformations, the VDR performs different protein–protein interactions, which then result in a characteristic functional profile. Most 1α,25(OH)2D3 analogues have been identified as agonists, a few are antagonists (e.g., ZK159222 and TEI‐9647), and only Gemini and some of its derivatives act under restricted conditions as non‐agonists. The functional profile of some 1α,25(OH)2D3 analogues, 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. J. Cell. Biochem. 88: 274–281, 2003.
Funding Information
  • the academy of finland (50319)