title: Pregnane X receptor (PXR), constitutive androstane receptor (CAR), and benzoate X receptor (BXR) define three pharmacologically distinct classes of nuclear receptors.
abstract: The NR1I subfamily of nuclear receptors contains a phylogenetically diverse array of receptors related to the mammalian pregnane X receptor (PXR) (NR1I2) and constitutive androstane receptor (CAR) (NR1I3). We have carried out an extensive comparative analysis of this subgroup with representatives from fish, birds, amphibians, and mammals. Four novel receptors were isolated from fish, dog, pig, and monkey for this study and combined with a previously reported set of related receptors including human PXR, rabbit PXR, mouse PXR, chicken CXR, frog benzoate X receptors (BXRalpha, BXRbeta), and human and mouse CAR. A broad range of xenobiotics, steroids, and bile acids were tested for their ability to activate the ligand binding domain of each receptor. Three distinct groups of receptors were identified based on their pharmacological profiles: 1) the PXRs were activated by a broad range of xenobiotics and, along with the mammalian PXRs, included the chicken and fish receptors; 2) the CARs were less promiscuous, had high basal activities, and were generally repressed rather than activated by those compounds that modulated their activity; and 3) the BXRs were selectively activated by a subset of benzoate analogs and are likely to be specialized receptors for this chemical class of ligands. The PXRs are differentiated from the other NR1I receptors by a stretch of amino acids between helices 1 and 3, which we designate the H1-3 insert. This insert was present in the mammalian, chicken, and fish PXRs but absent in the CARs and BXRs. Modeling studies suggest that the H1-3 insert contributes to the promiscuity of the PXRs by facilitating the unwinding of helices-6 and -7, thereby expanding the ligand binding pocket.
authors: Nuclear Receptor Discovery Research, GlaxoSmithKline, Research Triangle Park, North Carolina 27709, USA.
authors: Linda B
authors: LB
authors: Moore
authors: Jodi M
authors: JM
authors: Maglich
authors: David D
authors: DD
authors: McKee
authors: Bruce
authors: B
authors: Wisely
authors: Timothy M
authors: TM
authors: Willson
authors: Steven A
authors: SA
authors: Kliewer
authors: Millard H
authors: MH
authors: Lambert
authors: John T
authors: JT
authors: Moore
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001647:Bile Acids and Salts / Q000494:pharmacology; D001665:Binding Sites; D002645:Chickens; D003001:Cloning, Molecular; D000090702:Constitutive Androstane Receptor; D004285:Dogs; D019143:Evolution, Molecular; D000882:Haplorhini; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D010802:Phylogeny; D000077297:Pregnane X Receptor; D017433:Protein Structure, Secondary; D011817:Rabbits; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D011987:Receptors, Steroid / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D016415:Sequence Alignment; D013256:Steroids / Q000494:pharmacology; D013552:Swine; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D014162:Transfection; D015262:Xenobiotics / Q000494:pharmacology; D029867:Xenopus Proteins; D014982:Xenopus laevis; D015027:Zebrafish
chemical_list: D001647:Bile Acids and Salts; D000090702:Constitutive Androstane Receptor; C000625852:NR1I2 protein, human; C000716327:NR1I3 protein, human; C000625853:Nr1i2 protein, mouse; C000625854:Nr1i2 protein, rat; C000716328:Nr1i3 protein, mouse; C000716329:Nr1i3 protein, rat; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D013256:Steroids; D014157:Transcription Factors; D015262:Xenobiotics; D029867:Xenopus Proteins; C112210:benzoate X receptor, Xenopus