Central role of VDR conformations for understanding selective actions of vitamin D3 analogues

The vitamin D-3 receptor (VDR) acts primarily as a heterodimer with the retinoid X receptor (RXR) on different types of 1 alpha ,25-dihydroxyvitamin D-3 (1 alpha ,25(OH)(2)D-3) response elements (VDREs). Therefore, DNA-bound VDR-RXR heterodimers can be considered as the molecular switches of 1 alpha ,25(OH)(2)D-3 signalling. Functional conformations of the VDR within these molecular switches appear to be of central importance for describing the biologic actions of 1 alpha ,25(OH)(2)D-3 and its analogues. Moreover, VDR conformations provide a molecular basis for understanding the potential selective profile of VDR agonists, which is critical for a therapeutic application. This review discusses VDR conformations and their selective stabilization by 1 alpha ,25(OH)(2)D-3 and its analogues, such as EB1089 and Gemini, as a monomer in solution or as a heterodimer with RXR bound to different VDREs and complexed with coactivator or corepressor proteins. (C) 2001 Elsevier Science Inc. All rights reserved.