title: 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.
abstract: BACKGROUND
  The 1α,25-dihydroxy-3-epi-vitamin-D3 (1α,25(OH)2-3-epi-D3), a natural metabolite of the seco-steroid vitamin D3, 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-D3 is tissue-specific and exhibits lowest calcemic effect compared to that induced by 1α,25(OH)2D3. To further unveil the structural mechanism and structure-activity relationships of 1α,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).
  
  
  RESULTS
  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)2D3. 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-D3 in primary human keratinocytes and biochemical properties are comparable to 1α,25(OH)2D3.
  
  
  CONCLUSIONS
  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)2D3 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)2D3.
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), U964/Centre National de Recherche Scientifique (CNRS) UMR 7104/Université de Strasbourg, Illkirch, France.
authors.forename: Ferdinand
authors.initials: F
authors.lastname: Molnár
authors.forename: Rita
authors.initials: R
authors.lastname: Sigüeiro
authors.forename: Yoshiteru
authors.initials: Y
authors.lastname: Sato
authors.forename: Clarisse
authors.initials: C
authors.lastname: Araujo
authors.forename: Inge
authors.initials: I
authors.lastname: Schuster
authors.forename: Pierre
authors.initials: P
authors.lastname: Antony
authors.forename: Jean
authors.initials: J
authors.lastname: Peluso
authors.forename: Christian
authors.initials: C
authors.lastname: Muller
authors.forename: Antonio
authors.initials: A
authors.lastname: Mouriño
authors.forename: Dino
authors.initials: D
authors.lastname: Moras
authors.forename: Natacha
authors.initials: N
authors.lastname: Rochel
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002762:Cholecalciferol / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D018922:HL-60 Cells; D006801:Humans; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D018167:Receptors, Calcitriol / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D018167:Receptors, Calcitriol; D002762:Cholecalciferol