Pregnane X Receptor (PXR), Constitutive Androstane Receptor (CAR), and Benzoate X Receptor (BXR) Define Three Pharmacologically Distinct Classes of Nuclear Receptors
| Autor: | Linda B. Moore, John T. Moore, Timothy M. Willson, Millard H. Lambert, Bruce Wisely, Steven A. Kliewer, D.D. McKee, Jodi M. Maglich |
|---|---|
| Rok vydání: | 2002 |
| Předmět: |
Models
Molecular Receptors Steroid Swine Molecular Sequence Data Receptors Cytoplasmic and Nuclear Xenopus Proteins Retinoid X receptor Biology Transfection Protein Structure Secondary Xenobiotics Bile Acids and Salts Evolution Molecular Mice Xenopus laevis Liver X receptor beta Dogs Endocrinology Constitutive androstane receptor Animals Humans Amino Acid Sequence Cloning Molecular Receptor Molecular Biology Constitutive Androstane Receptor Phylogeny Zebrafish Pregnane X receptor Binding Sites Molecular Structure Pregnane X Receptor Liver X receptor alpha Haplorhini General Medicine Rats Biochemistry Nuclear receptor Steroids Estrogen-related receptor gamma Rabbits Chickens Sequence Alignment Transcription Factors |
| Zdroj: | Molecular Endocrinology. 16:977-986 |
| ISSN: | 1944-9917 0888-8809 |
| DOI: | 10.1210/mend.16.5.0828 |
| Popis: | 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 (BXRα, BXRβ), 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|