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Background  The 1α,25-dihydroxy-3-epi-vitamin-D 3  (1α,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 1α,25(OH) 2 -3-epi-D 3  is tissue-specific and exhibits lowest calcemic effect compared to that induced by 1α,25(OH) 2 D 3 . To further unveil the structural mechanism and structure-activity relationships of 1α,25(OH) 2 -3-epi-D 3  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 1α,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 1α,25(OH) 2 -3-epi-D 3  in primary human keratinocytes and biochemical properties are comparable to 1α,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 1α,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 1α,25(OH) 2 D 3 .

plos one

1α,25(OH)2-3-Epi-Vitamin D3, a Natural Physiological Metabolite of Vitamin D3: Its Synthesis, Biological Activity and Crystal Structure with Its Receptor