title: Correlation between secosteroid-induced vitamin D receptor activity in melanoma cells and computer-modeled receptor binding strength.
abstract: To define the interaction of novel secosteroids produced by the action of cytochrome P450scc with vitamin D receptor (VDR), we used a human melanoma line overexpressing VDR fused with enhanced green fluorescent protein (EGFP) and tested the ligand induced translocation of VDR from the cytoplasm to the nucleus. Hydroxyderivatives of vitamin D(3) with a full length (D(3)) side chain and hydroxy-secosteroids with a shortened side chain (pD) stimulated VDR translocation and inhibited proliferation, however, with different potencies. In general the D(3) were more potent than pD analogues. Molecular modeling of the binding of the secosteroids to the VDR genomic binding pocket (G-pocket) correlated well with the experimental data for VDR translocation. In contrast, docking scores for the non-genomic binding site of the VDR were poor. In conclusion, both the length of the side chain and the number and position of hydroxyl groups affect the activation of VDR by novel secosteroids.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
authors.forename: Tae-Kang
authors.initials: TK
authors.lastname: Kim
authors.forename: Jin
authors.initials: J
authors.lastname: Wang
authors.forename: Zorica
authors.initials: Z
authors.lastname: Janjetovic
authors.forename: Jianjun
authors.initials: J
authors.lastname: Chen
authors.forename: Robert C
authors.initials: RC
authors.lastname: Tuckey
authors.forename: Minh N
authors.initials: MN
authors.lastname: Nguyen
authors.forename: Edith K Y
authors.initials: EK
authors.lastname: Tang
authors.forename: Duane
authors.initials: D
authors.lastname: Miller
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Andrzej T
authors.initials: AT
authors.lastname: Slominski
mesh_terms: D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002762:Cholecalciferol / Q000494:pharmacology; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000378:metabolism; D003198:Computer Simulation; D000078404:Epidermal Cells; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D011485:Protein Binding / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D018167:Receptors, Calcitriol / Q000378:metabolism*; D012632:Secosteroids / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D018167:Receptors, Calcitriol; D012632:Secosteroids; D002762:Cholecalciferol; D002786:Cholesterol Side-Chain Cleavage Enzyme