title: Probing a water channel near the A-ring of receptor-bound 1 alpha,25-dihydroxyvitamin D3 with selected 2 alpha-substituted analogues.
abstract: The crystal structure of the vitamin D receptor (VDR) in complex with 1 alpha,25(OH)2D3 revealed the presence of several water molecules near the A-ring linking the ligand C-2 position to the protein surface. Here, we report the crystal structures of the human VDR ligand binding domain bound to selected C-2 alpha substituted analogues, namely, methyl, propyl, propoxy, hydroxypropyl, and hydroxypropoxy. These specific replacements do not modify the structure of the protein or the ligand, but with the exception of the methyl substituent, all analogues affect the presence and/or the location of the above water molecules. The integrity of the channel interactions and specific C-2 alpha analogue directed additional interactions correlate with the binding affinity of the ligands. In contrast, the resulting loss or gain of H-bonds does not reflect the magnitude of HL60 cell differentiation. Our overall findings highlight a rational approach to the design of more potent ligands by building in features revealed in the crystal structures.
authors.affiliation: Laboratoire de Biologie et Génomique Structurales, UMR 7104, Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, 1, Rue Laurent Fries, BP 10142, 67404 Illkirch Cedex, France.
authors.forename: Shinji
authors.initials: S
authors.lastname: Hourai
authors.forename: Toshie
authors.initials: T
authors.lastname: Fujishima
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kittaka
authors.forename: Yoshitomo
authors.initials: Y
authors.lastname: Suhara
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Takayama
authors.forename: Natacha
authors.initials: N
authors.lastname: Rochel
authors.forename: Dino
authors.initials: D
authors.lastname: Moras
mesh_terms: D001665:Binding Sites; D002117:Calcitriol / Q000737:chemistry* / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D003460:Crystallization; D018922:HL-60 Cells; D006801:Humans; D006860:Hydrogen Bonding; D008024:Ligands; D008968:Molecular Conformation; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D018167:Receptors, Calcitriol / Q000737:chemistry* / Q000187:drug effects; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014867:Water / Q000737:chemistry
chemical_list: D008024:Ligands; D018167:Receptors, Calcitriol; D014867:Water; D002117:Calcitriol