ArticleMolecular and cellular biology2002
A structural model of the constitutive androstane receptor defines novel interactions that mediate ligand-independent activity.
Article in Molecular and cellular biology, 2002. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 47 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
47 citing papers in PubMed, 109 citations in OpenAlex.
- SMRT regulation of nuclear receptors orchestrates bile acid homeostasis.Experimental & molecular medicine · 2026Article
- Impact of Persistent Endocrine-Disrupting Chemicals on Human Nuclear Receptors: Insights from In Silico and Experimental Characterization.International journal of molecular sciences · 2025Article
- HNF4α contributes to hepatic CAR dysfunction in polymicrobial sepsis.Frontiers in immunology · 2025Article
- Liver matrin-3 protects mice against hepatic steatosis and stress response via constitutive androstane receptor.Molecular metabolism · 2024Article
- Statistical Analysis of Protein-Ligand Interaction Patterns in Nuclear Receptor RORγ.Frontiers in molecular biosciences · 2022Article
- Discrepancy in interactions and conformational dynamics of pregnane X receptor (PXR) bound to an agonist and a novel competitive antagonist.Computational and structural biotechnology journal · 2022Article
- Pregnane X Receptor (PXR) Polymorphisms and Cancer Treatment.Biomolecules · 2021Review
- Article
- Strategies for developing pregnane X receptor antagonists: Implications from metabolism to cancer.Medicinal research reviews · 2020Review
- Drug discovery technologies to identify and characterize modulators of the pregnane X receptor and the constitutive androstane receptor.Drug discovery today · 2019Review
- Nuclear Receptor Metabolism of Bile Acids and Xenobiotics: A Coordinated Detoxification System with Impact on Health and Diseases.International journal of molecular sciences · 2018Review
- In vivo genome-wide binding interactions of mouse and human constitutive androstane receptors reveal novel gene targets.Nucleic acids research · 2018Article
- Enteric Microbiota⁻Gut⁻Brain Axis from the Perspective of Nuclear Receptors.International journal of molecular sciences · 2018Review
- A current structural perspective on PXR and CAR in drug metabolism.Expert opinion on drug metabolism & toxicology · 2018Review
- CINPA1 binds directly to constitutive androstane receptor and inhibits its activity.Biochemical pharmacology · 2018Article
- Allosteric pathways in nuclear receptors - Potential targets for drug design.Pharmacology & therapeutics · 2018Review
- Using TR-FRET to Investigate Protein-Protein Interactions: A Case Study of PXR-Coregulator Interaction.Advances in protein chemistry and structural biology · 2018Review
- DNA-induced unfolding of the thyroid hormone receptor α A/B domain through allostery.FEBS open bio · 2017Article
- Mechanisms of xenobiotic receptor activation: Direct vs. indirect.Biochimica et biophysica acta · 2016Review
- Regulation of PXR and CAR by protein-protein interaction and signaling crosstalk.Expert opinion on drug metabolism & toxicology · 2016Review
Corrections and comments
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Authors and funding
7 authors at 1 institution in 2 countries.
Funding
Abstract
Unlike classical nuclear receptors that require ligand for transcriptional activity, the constitutive androstane receptor (CAR) is active in the absence of ligand. To determine the molecular contacts that underlie this constitutive activity, we created a three-dimensional model of CAR and verified critical structural features by mutational analysis. We found that the same motifs that facilitate ligand-dependent activity in classical receptors also mediated constitutive activity in CAR. This raises a critical question: how are these motifs maintained in an active conformation in unliganded CAR? The model identified several novel interactions that account for this activity. First, CAR possesses a short loop between helix 11 and the transactivation domain (helix 12), as well as a short carboxy-terminal helix. Together, these features favor ligand-independent docking of the transactivation domain in a position that is characteristic of ligand-activated receptors. Second, this active conformation is further stabilized by a charge-charge interaction that anchors the carboxy-terminal activation domain to helix 4. Mutational analysis of these interactions provides direct experimental support for this model. We also show that ligand-mediated repression of constitutive activity reflects both a displacement of coactivator and a recruitment of corepressor. Our data demonstrate that CAR utilizes the same conserved structural motifs and coregulator proteins as originally defined for classical nuclear receptors. Despite these remarkable similarities, our model demonstrates how a few critical changes in CAR can dramatically reverse the transcriptional activity of this protein.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.