A Structural Basis for Constitutive Activity in the Human CAR/RXRα Heterodimer

Xu, Renfeng; Lambert, Millard H.; Wisely, Bruce; Warren, Erin N.; Weinert, Emily E.; Waitt, Greg; Williams, Jon D.; Collins, Jon L.; Moore, Linda B.; Willson, Timothy M.; Moore, John T.

doi:10.1016/j.molcel.2004.11.042

Cited by 208 publications

(276 citation statements)

References 55 publications

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“…Chemicals that activate or repress CAR in cell-based assays are generally considered ligands. They were found to bind the LBD of CAR in X-ray crystal structures (Suino et al, 2004;Xu et al, 2004). Although EGF repressed ligand activation of CAR (e.g., by ligands such as TCPOBOP and CITCO), unlike PB, these ligands did not repress EGF signaling at the EGFR (Koike et al, 2007;Shizu et al, 2017).…”

Section: Phenobarbital and Nuclear Receptorsmentioning

confidence: 99%

Phenobarbital Meets Phosphorylation of Nuclear Receptors

Negishi

2017

Drug Metab Dispos

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Phenobarbital was the first therapeutic drug to be characterized for its induction of hepatic drug metabolism. Essentially at the same time, cytochrome P450, an enzyme that metabolizes drugs, was discovered. After nearly 50 years of investigation, the molecular target of phenobarbital induction has now been delineated to phosphorylation at threonine 38 of the constitutive androstane receptor (NR1I3), a member of the nuclear receptor superfamily. Determining this mechanism has provided us with the molecular basis to understand drug induction of drug metabolism and disposition. Threonine 38 is conserved as a phosphorylation motif in the majority of both mouse and human nuclear receptors, providing us with an opportunity to integrate diverse functions of nuclear receptors. Here, I review the works and accomplishments of my laboratory at the National Institutes of Health National Institute of Environmental Health Sciences and the future research directions of where our study of the constitutive androstane receptor might take us.

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Section: Phenobarbital and Nuclear Receptorsmentioning

confidence: 99%

Phenobarbital Meets Phosphorylation of Nuclear Receptors

Negishi

2017

Drug Metab Dispos

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“…In summary, NCOA binding molecules include many kinds of nuclear receptors, including androgen receptor, estrogen receptor, nuclear receptor subfamily 1, group I member 3 (NR1I3/CAR), bile acid receptor, and pregnane X receptor. [57][58][59][60][61] Other detailed investigation into the MoRFs with similar-fold partners was performed and discussed in our previous work. 52 …”

Section: Morf Sets With Partner Pairs Exhibiting Similar Foldsmentioning

confidence: 99%

Exploring the binding diversity of intrinsically disordered proteins involved in one‐to‐many binding

et al. 2013

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Molecular recognition features (MoRFs) are intrinsically disordered protein regions that bind to partners via disorder-to-order transitions. In one-to-many binding, a single MoRF binds to two or more different partners individually. MoRF-based one-to-many protein-protein interaction (PPI) examples were collected from the Protein Data Bank, yielding 23 MoRFs bound to 2-9 partners, with all pairs of same-MoRF partners having less than 25% sequence identity. Of these, 8 MoRFs were bound to 2-9 partners having completely different folds, whereas 15 MoRFs were bound to 2-5 partners having the same folds but with low sequence identities. For both types of partner variation, backbone and side chain torsion angle rotations were used to bring about the conformational changes needed to enable close fits between a single MoRF and distinct partners. Alternative splicing events (ASEs) and posttranslational modifications (PTMs) were also found to contribute to distinct partner binding. Because ASEs and PTMs both commonly occur in disordered regions, and because both ASEs and PTMs are often tissue-specific, these data suggest that MoRFs, ASEs, and PTMs may collaborate to alter PPI networks in different cell types. These data enlarge the set of carefully studied MoRFs that use inherent flexibility and that also use ASE-based and/or PTM-based surface modifications to enable the same disordered segment to selectively associate with two or more partners. The small number of residues involved in MoRFs and in their modifications by ASEs or PTMs may simplify the evolvability of signaling network diversity.

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“…Together, our studies underscore the complexity of regulation of PXR-and CAR-shared target gene networks and provide important information on the potential mechanism of interindividual variability in drug metabolism. These data together with the recently solved crystal structures of PXR and CAR (Watkins et al, 2001;Shan et al, 2004;Suino et al, 2004;Xu et al, 2004) will likely aid in the rational design of more specific CAR inverse agonists, which due to their likely ability to modulate serum thyroid hormone levels are viewed as potential antiobesity drugs (Maglich et al, 2004;Qatanani et al, 2005).…”

mentioning

confidence: 98%

The Ratio of Constitutive Androstane Receptor to Pregnane X Receptor Determines the Activity of Guggulsterone against the Cyp2b10 Promoter

Ding

Staudinger²

2005

J Pharmacol Exp Ther

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Guggulsterone is the active ingredient in gugulipid, an organic extract of the Commiphora mukul plant. Gugulipid has been used for nearly 3000 years in Ayurvedic medicine, mainly as a treatment for arthritis. Herbal practitioners currently use gugulipid therapy in conditions as diverse as rheumatism, coronary artery disease, arthritis, hyperlipidemia, acne, and obesity. The active ingredient in gugulipid is guggulsterone, a plant sterol compound recently identified as a pregnane X receptor (PXR; NR1I2) ligand. We show herein that guggulsterone treatment represses the expression of cytochrome P450 2b10 (Cyp2b10) gene expression by inhibiting constitutive androstane receptor (CAR; NR1I3) activity in hepatocytes lacking functional PXR (PXR-knockout). We also show that PXR-CAR cross-talk determines the net activity of guggulsterone treatment toward Cyp2b10 gene expression. Using mammalian two-hybrid assays, we show that treatment with guggulsterone differentially affects protein cofactor recruitment to these two nuclear receptors. These data identify guggulsterone as an inverse agonist of the nuclear receptor CAR. When viewed together with the data showing that PXR and CAR expression is highly variable in different ethnic populations and that CAR expression is under the control of a circadian rhythm, our data provide important insight into the molecular mechanism of interindividual variability of drug metabolism. These data, together with the recent resolution of the crystal structures of PXR and CAR, will likely aid in the rational design of more specific CAR inverse agonists that are currently viewed as potential antiobesity drugs.Gugulipid is an herbal remedy derived from the gum resin of the Commiphora mukul tree. Gugulipid has been used in Ayurvedic medicine mainly to treat arthritis and inflammation. A number of clinical trials performed in India determined that gugulipid treatment produces favorable lipid profiles in patients with high cholesterol Gopal et al., 1986;Nityanand et al., 1989). This finding has led to the widespread import and use of gugulipid extract in humans as a cholesterol-lowering agent sold in nutrition centers without a prescription in western societies. A recent human clinical trial has raised questions regarding the efficacy of gugulipid extract in lowering serum cholesterol (Szapary et al., 2003). Moreover, our laboratory has recently demonstrated that the use of gugulipid induces the expression and activity of drug-metabolizing cytochrome P450 genes through activation of the nuclear receptor protein PXR in cells (Brobst et al., 2004). The notion that gugulipid produces herb-drug interactions in humans is further supported by the results of a small, well controlled study that revealed significantly reduced (P Ͻ 0.01) peak plasma concentrations of either diltiazem or propranololin in volunteer patients cofed 1 g of gugulipid in comparison with those that received one of these drugs in combination with a placebo (Dalvi et al., 1994).The active ingredients in gugulipid are the ket...

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A Structural Basis for Constitutive Activity in the Human CAR/RXRα Heterodimer

Cited by 208 publications

References 55 publications

Phenobarbital Meets Phosphorylation of Nuclear Receptors

Phenobarbital Meets Phosphorylation of Nuclear Receptors

Exploring the binding diversity of intrinsically disordered proteins involved in one‐to‐many binding

The Ratio of Constitutive Androstane Receptor to Pregnane X Receptor Determines the Activity of Guggulsterone against the Cyp2b10 Promoter

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