title: 19F NMR study on the complex of fluorinated vitamin D derivatives with vitamin D receptor: elucidation of the conformation of vitamin D ligands accommodated in the receptor.
abstract: Nuclear receptors mediate allosteric communications where ligand binding initiates a cascade of signal transduction. The interaction of vitamin D with vitamin D receptor (VDR) was investigated by (19)F NMR spectroscopy of the complexes of three fluorinated vitamin D derivatives with the full-length rat VDR-LBD. In the (19)F NMR spectra of the VDR-ligand complexes, the A-ring of 4,4-difluoro-1,25(OH)2D3 was revealed to adopt β-conformation in the VDR in solution, and the spectra were shown to be dependent on the dissociation constant. While the complex of 4,4-difluoro-1,25(OH)2D3 with VDR exhibited a clear distinguishable (19)F NMR spectrum, those of (19)F-1,25(OH)2D3 stereoisomers, which have 10-fold higher VDR affinity than 4,4-difluoro-1,25(OH)2D3, did not. The solid-phase NMR technique was useful for (19)F-1,25(OH)2D3 stereoisomers. The fluorinated vitamin D derivatives showed marked changes in the chemical shift (Δ4-19.7 ppm) upon VDR-complex formation, and the ab initio MO method suggested that van der Waals interactions play a major role in the complex formation.
authors.affiliation: Graduate School of Medical and Dental Sciences, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Morizono
mesh_terms: D000495:Allosteric Site; D000818:Animals; D002117:Calcitriol / Q000737:chemistry; D002244:Carbon / Q000737:chemistry; D002762:Cholecalciferol / Q000031:analogs & derivatives / Q000737:chemistry; D003461:Crystallography; D005461:Fluorine / Q000737:chemistry; D006859:Hydrogen / Q000737:chemistry; D006878:Hydroxides / Q000737:chemistry; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008956:Models, Chemical; D008968:Molecular Conformation; D015394:Molecular Structure; D051381:Rats; D018167:Receptors, Calcitriol / Q000737:chemistry*; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000737:chemistry; D047392:beta-Cyclodextrins / Q000737:chemistry
chemical_list: C419448:19-fluoro-1,25-dihydroxyvitamin D3; C467589:4,4-difluoro-1,25-dihydroxyvitamin D3; D006878:Hydroxides; D008024:Ligands; D018167:Receptors, Calcitriol; D047392:beta-Cyclodextrins; D014807:Vitamin D; D002762:Cholecalciferol; D005461:Fluorine; C000609658:heptakis(2,3,6-tri-O-methyl)-beta-cyclodextrin; D002244:Carbon; D006859:Hydrogen; C031356:hydroxide ion; D002117:Calcitriol