Journal
PLOS ONE
Volume 6, Issue 3, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0018124
Keywords
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Funding
- CNRS
- INSERM
- ULP
- European Commission [LSHG-CT-2006-031220]
- Spanish Ministry of Education and Science [SAF2007-67205]
- Xunta de Galicia [INCITE08PXIB-209130PR, ACEUIC-2006/XA050]
- Spanish MEC
- Academy of Finland [128226]
- Academy of Finland (AKA) [128226, 128226] Funding Source: Academy of Finland (AKA)
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Background: The 1 alpha,25-dihydroxy-3-epi-vitamin-D-3 (1 alpha,25(OH)(2)-3-epi-D-3), a natural metabolite of the seco-steroid vitamin D-3, exerts its biological activity through binding to its cognate vitamin D nuclear receptor (VDR), a ligand dependent transcription regulator. In vivo action of 1 alpha,25(OH)(2)-3-epi-D-3 is tissue-specific and exhibits lowest calcemic effect compared to that induced by 1 alpha,25(OH)(2)D-3. To further unveil the structural mechanism and structure-activity relationships of 1 alpha,25(OH)(2)-3-epi-D3 and its receptor complex, we characterized some of its in vitro biological properties and solved its crystal structure complexed with human VDR ligand-binding domain (LBD). Methodology/Principal Findings: In the present study, we report the more effective synthesis with fewer steps that provides higher yield of the 3-epimer of the 1 alpha,25(OH)(2)D-3. We solved the crystal structure of its complex with the human VDR-LBD and found that this natural metabolite displays specific adaptation of the ligand-binding pocket, as the 3-epimer maintains the number of hydrogen bonds by an alternative water-mediated interaction to compensate the abolished interaction with Ser278. In addition, the biological activity of the 1 alpha,25(OH)(2)-3-epi-D-3 in primary human keratinocytes and biochemical properties are comparable to 1 alpha,25(OH)(2)D-3. Conclusions/Significance: The physiological role of this pathway as the specific biological action of the 3-epimer remains unclear. However, its high metabolic stability together with its significant biologic activity makes this natural metabolite an interesting ligand for clinical applications. Our new findings contribute to a better understanding at molecular level how natural metabolites of 1 alpha,25(OH)(2)D-3 lead to significant activity in biological systems and we conclude that the C3-epimerization pathway produces an active metabolite with similar biochemical and biological properties to those of the 1 alpha,25(OH)(2)D-3.
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