Related Experiment Video
Updated: Jul 30, 2026

A Method of Trigonometric Modelling of Seasonal Variation Demonstrated with Multiple Sclerosis Relapse Data
Published on: December 9, 2015
Gene regulatory potential of 1alpha,25-dihydroxyvitamin D(3) analogues with two side chains
Y Bury1, M Herdick, M R Uskokovic
1Institut für Physiologische Chemie I and Biomedizinisches Forschungszentrum, Heinrich-Heine-Universität Düsseldorf, Postfach 10 10 07, D-40001 Düsseldorf, Germany.
Abstract:
The nuclear hormone 1alpha,25-dihydroxyvitamin D(3) (1alpha,25(OH)(2)D(3)) acts through the transcription factor vitamin D receptor (VDR) via combined contact with the retinoid X receptor (RXR), coactivator proteins, and specific DNA binding sites (VDREs). Ligand-mediated conformational changes of the VDR are the core of the molecular switch of nuclear 1alpha,25(OH)(2)D(3) signalling. Studying the interaction of 1alpha,25(OH)(2)D(3) analogues with this molecular switch should allow the characterization of their potential selective biological profile. A 1alpha,25(OH)(2)D(3) analogue with two side chains (Ro27-2310 or Gemini) was found to stabilize functional VDR conformations and VDR-RXR heterodimers on a VDRE with a slightly lower sensitivity than the natural hormone. A 19-nor derivative of Gemini (Ro27-5646) showed similar sensitivity whereas 5,6-trans (Ro27-6462) 3-epi (Ro27-5840) and 1alpha-fluoro (Ro27-3752) derivatives were equal to each other, but approximately 30-times less sensitive than Gemini. A des-C,D derivative of Gemini (Ro28-1909) showed only residual activity at maximal concentrations. In contrast to 1alpha,25(OH)(2)D(3), Gemini and its derivatives showed a differential preference in stabilizing VDR conformations which was found to be modulated by DNA coactivator and corepressor proteins. An analysis of the gene regulatory potential of the VDR agonists in cellular reporter gene systems demonstrated the same ranking as in the in vitro systems, but Gemini and its 19-nor derivative were found to be more sensitive than 1alpha,25(OH)(2)D(3) which indicates that the natural hormone is selectively metabolized. This study used straightforward methods for the in vitro and ex vivo evaluation of the gene regulatory potential of 1alpha,25(OH)(2)D(3) analogues. Gemini was highlighted as an interesting drug candidate which could not be optimized through obvious chemical modifications in its A-ring. J. Cell. Biochem. Suppl. 36: 179-190, 2001.
Related Concept Videos
Covalently Linked Protein Regulators
These groups modify specific amino acids in a protein.
Cooperative Binding of Transcription Regulators
Master Transcription Regulators
Covalently Linked Protein Regulators
These groups modify specific amino acids in a protein.
TGF - β Signaling Pathway
Transducer Mechanism: Nuclear Receptors
About 48 different soluble family members of nuclear receptors are identified that can be divided into two main classes:

