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Vitamin D analogue-specific recruitment of vitamin D receptor coactivators
Laura L Issa1, Gary M Leong, Robert L Sutherland
1Bone and Mineral Program, Garvan Institute of Medical Research, St. Vincent's Hospital, Sydney, NSW, Australia.
Abstract:
Synthetic ligands for the vitamin D receptor (VDR) are potential therapeutic agents for metabolic, neoplastic, and autoimmune disorders. Some of these ligands have similar or more potent antiproliferative, yet reduced hypercalcemic actions, than calcitriol. However, the mechanisms for these differential actions have not been clearly defined. We hypothesized that these gene- and tissue-specific effects may relate to ligand-directed selective recruitment of transcriptional coactivators. To identify key elements in ligand structure that facilitate VDR-coactivator interactions, the current studies assessed the ability of the VDR to recruit the coactivators GRIP1 and RAC3 following activation by a series of 20-R- and 20-S (20-epi)-modified analogues. The strength of VDR-coactivator interactions was ligand-specific and did not always correlate with ligand-receptor binding affinity. In general, the 20-epi analogues enhanced these interactions, whereas the 20-R-modified analogues were less effective than calcitriol. The 16-ene,23-yne modification and fluorinated substituents to the side-chain attenuated interaction with coactivators. The enhanced ability of the VDR to recruit GRIP1 following activation by the 20-epi analogues was consistent with potentiation of 20-epi analogue-induced transactivation of the osteocalcin gene promoter by GRIP1. Overall, the structure of the ligand side-chain as well as its orientation seemed to affect the avidity of coactivator binding. These results suggest that selective recruitment of coactivators may contribute to gene- and tissue-specific effects of vitamin D analogues.
Insights
Synthetic vitamin D receptor (VDR) ligands show therapeutic promise. Ligand structure influences VDR
Area of Science:
- Biochemistry
- Molecular Biology
- Endocrinology
Background:
- Synthetic vitamin D receptor (VDR) ligands offer therapeutic potential for various diseases.
- Differential actions of VDR ligands, including antiproliferative and hypercalcemic effects, are not fully understood.
- Selective recruitment of transcriptional coactivators by VDR ligands is hypothesized to mediate gene- and tissue-specific effects.
Purpose of the Study:
- To investigate how ligand structure influences the interaction between the VDR and its coactivators.
- To identify structural elements in VDR ligands critical for VDR-coactivator complex formation.
- To correlate VDR-coactivator interactions with ligand-induced gene transactivation.
Main Methods:
- Synthesis and assessment of 20-R- and 20-S (20-epi)-modified VDR analogues.
- Evaluation of VDR's ability to recruit coactivators GRIP1 and RAC3 upon activation by these analogues.
- Analysis of VDR-coactivator binding affinity and its correlation with ligand-receptor binding.
- Assessment of coactivator potentiation of analogue-induced transactivation of the osteocalcin gene promoter.
Main Results:
- VDR-coactivator interaction strength was ligand-specific and did not always correlate with binding affinity.
- 20-epi analogues generally enhanced VDR-coactivator interactions compared to calcitriol.
- 20-R analogues were less effective than calcitriol in promoting VDR-coactivator interactions.
- Specific side-chain modifications (16-ene, 23-yne, fluorinated substituents) attenuated coactivator binding.
- Enhanced GRIP1 recruitment by 20-epi analogues correlated with potentiated osteocalcin gene promoter activity.
Conclusions:
- Ligand structure, particularly the side-chain and its orientation, significantly impacts VDR's avidity for coactivator binding.
- Selective recruitment of coactivators by VDR ligands is a key mechanism underlying their gene- and tissue-specific actions.
- These findings provide insights into the rational design of VDR-based therapeutics with improved efficacy and reduced side effects.