Pregnane X receptor (PXR), constitutive androstane receptor (CAR), and benzoate X receptor (BXR) define three pharmacologically distinct classes of nuclear receptors

Linda B. Moore, Jodi M. Maglich, David D. McKee, Bruce Wisely, Timothy M. Willson, Steven A. Kliewer, Millard H. Lambert, John T. Moore

Research output: Contribution to journalArticle

282 Citations (Scopus)

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 (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.

Original languageEnglish (US)
Pages (from-to)977-986
Number of pages10
JournalMolecular Endocrinology
Volume16
Issue number5
DOIs
StatePublished - 2002

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Benzoates
Cytoplasmic and Nuclear Receptors
Fishes
Chickens
Xenobiotics
Ligands
Mechanoreceptors
Amphibians
Bile Acids and Salts
Anura
Birds
Haplorhini
Mammals
Swine
Steroids
Pharmacology
Dogs
Rabbits
Amino Acids
constitutive androstane receptor

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology, Diabetes and Metabolism

Cite this

Pregnane X receptor (PXR), constitutive androstane receptor (CAR), and benzoate X receptor (BXR) define three pharmacologically distinct classes of nuclear receptors. / Moore, Linda B.; Maglich, Jodi M.; McKee, David D.; Wisely, Bruce; Willson, Timothy M.; Kliewer, Steven A.; Lambert, Millard H.; Moore, John T.

In: Molecular Endocrinology, Vol. 16, No. 5, 2002, p. 977-986.

Research output: Contribution to journalArticle

Moore, Linda B. ; Maglich, Jodi M. ; McKee, David D. ; Wisely, Bruce ; Willson, Timothy M. ; Kliewer, Steven A. ; Lambert, Millard H. ; Moore, John T. / Pregnane X receptor (PXR), constitutive androstane receptor (CAR), and benzoate X receptor (BXR) define three pharmacologically distinct classes of nuclear receptors. In: Molecular Endocrinology. 2002 ; Vol. 16, No. 5. pp. 977-986.
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