title: Ligand specificity of constitutive androstane receptor as probed by induced-fit docking and mutagenesis.
abstract: Constitutive androstane receptor (CAR, NR1I3) belongs to the nuclear receptor family of transcription factors and acts as a chemical sensor of drugs and endogenous compounds. The ligand-binding preferences of CAR are diverse, and more importantly, there are significant species differences in ligand specificity. Here, we show that while certain residues are critical for the basal activity of mouse CAR (mCAR) and/or affect the binding of all tested ligands, mutation of some ligand-binding pocket (LBP) residues (e.g., F171 and Y336) paradoxically decreased the activity of a specific ligand while increasing that of others. Comparisons to previously reported human CAR (hCAR) residues indicated that the function of key CAR residues (e.g., N175, L253) is dramatically different between species. The docking results provide some mechanistic rationale for the ability of 17alpha-ethinyl-3,17beta-estradiol (EE2) to both activate mCAR and repress hCAR.
authors.affiliation: Structural Bioinformatics Laboratory, Department of Biochemistry and Pharmacy, Abo Akademi University, Tykistökatu 6, FI-20520 Turku, Finland.
authors.forename: Susanna
authors.initials: S
authors.lastname: Repo
authors.forename: Johanna
authors.initials: J
authors.lastname: Jyrkkärinne
authors.forename: Juha T
authors.initials: JT
authors.lastname: Pulkkinen
authors.forename: Reino
authors.initials: R
authors.lastname: Laatikainen
authors.forename: Paavo
authors.initials: P
authors.lastname: Honkakoski
authors.forename: Mark S
authors.initials: MS
authors.lastname: Johnson
mesh_terms: D000818:Animals; D003022:Clotrimazole / Q000494:pharmacology; D000090702:Constitutive Androstane Receptor; D018360:Crystallography, X-Ray; D004997:Ethinyl Estradiol / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008024:Ligands; D008731:Methoxychlor / Q000494:pharmacology; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D016296:Mutagenesis; D017433:Protein Structure, Secondary; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors* / Q000235:genetics*; D012680:Sensitivity and Specificity; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000235:genetics*
chemical_list: D000090702:Constitutive Androstane Receptor; D008024:Ligands; C000716327:NR1I3 protein, human; C000716328:Nr1i3 protein, mouse; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D004997:Ethinyl Estradiol; D003022:Clotrimazole; D008731:Methoxychlor