Related Experiment Video

Updated: Aug 20, 2026

Detecting the Ligand-binding Domain Dimerization Activity of Estrogen Receptor Alpha Using the Mammalian Two-Hybrid Assay
09:07

Detecting the Ligand-binding Domain Dimerization Activity of Estrogen Receptor Alpha Using the Mammalian Two-Hybrid Assay

Published on: December 19, 2018

Structure of the murine constitutive androstane receptor complexed to androstenol: a molecular basis for inverse

Li Shan1, Jeremy Vincent, Joseph S Brunzelle

  • 1Biochemistry, Cellular and Molecular Biology, University of Tennessee, Knoxville, TN 37996, USA.

Molecular Cell
|December 22, 2004
PubMed

Insights

The constitutive androstane receptor (CAR) is a key regulator of drug metabolism. This study reveals the crystal structure of CAR bound to androstenol, uncovering a novel inverse agonism mechanism.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • The nuclear receptor CAR (constitutive androstane receptor) is a xenobiotic-responsive transcription factor.
  • CAR regulates drug and bilirubin clearance, and is implicated in cocaine and acetaminophen toxicity.
  • CAR exhibits a unique 'reverse' mechanism of action, being active without ligand and inactive with inverse agonists.

Purpose of the Study:

  • To determine the crystal structure of murine CAR bound to the inverse agonist androstenol.
  • To elucidate the molecular mechanism of CAR inverse agonism.

Main Methods:

  • X-ray crystallography
  • Structural analysis of murine CAR bound to androstenol.

Main Results:

  • The crystal structure of murine CAR bound to androstenol was determined.
  • Androstenol binds to the CAR ligand-binding pocket but does not interact with helix H12/AF2.
  • Ligand binding induces a kink between helices H10 and H11, disrupting the salt bridge that stabilizes the active conformation.

Conclusions:

  • This study reveals a distinct mechanism of inverse agonism for CAR, differing from traditional antagonists.
  • The findings offer new strategies for modulating CAR activity.

More Related Videos

Optimizing the Genetic Incorporation of Chemical Probes into GPCRs for Photo-crosslinking Mapping and Bioorthogonal Chemistry in Live Mammalian Cells14:02

Optimizing the Genetic Incorporation of Chemical Probes into GPCRs for Photo-crosslinking Mapping and Bioorthogonal Chemistry in Live Mammalian Cells

Published on: April 9, 2018

Quantifying Agonist Activity at G Protein-coupled Receptors11:45

Quantifying Agonist Activity at G Protein-coupled Receptors

Published on: December 26, 2011

Related Concept Videos

The Two-State Receptor Model01:29

The Two-State Receptor Model

The two-state receptor model explains a drug's interaction with receptors, such as G protein-coupled receptors and ligand-gated ion channels, to induce or inhibit a biological response. When no natural ligands are present, a receptor exists in an equilibrium of inactive (Ri) and active (Ra) conformations. The inactive form does not produce a response, while the active form generates a basal effect known as constitutive activity.
The binding affinity of a drug determines its interaction with one...
Drug-Receptor Interaction: Agonist01:25

Drug-Receptor Interaction: Agonist

Agonists are drugs that interact with specific receptors in the body to produce a biological response. When an agonist binds to a receptor, it activates or enhances the receptor's function, leading to physiological effects. The interaction between agonist drugs and receptors is crucial for their therapeutic action in various medical treatments.
Agonists can bind to receptors in different ways. Some agonists bind directly to the receptor's active site, mimicking the endogenous ligand's action.
Adrenergic Agonists: Chemistry and Structure-Activity Relationship01:16

Adrenergic Agonists: Chemistry and Structure-Activity Relationship

Adrenergic agonists' structure-activity relationship (SAR) determines their selectivity and efficacy. These agonists comprise a phenylethylamine moiety with an aromatic ring and an ethylamine side chain.
Aromatic ring substitutions: Substituting the aromatic ring with –OH groups at positions 3 and 4 yields catecholamines (e.g., epinephrine), which have a high affinity for adrenoceptors. Hydrogen bonding between –OH groups and receptors enhances adrenergic activity.
Separation of the aromatic...
Drug-Receptor Interactions01:29

Drug-Receptor Interactions

Drug-receptor interaction describes the binding of receptors by drugs, but not all drug-receptor interactions result in activation and tissue response. For instance, the binding of agonists activates the receptor to generate a cellular reaction, while antagonists bind to receptors without causing their activation.
Several parameters, such as the drug's affinity for its receptor and its efficacy, which is its ability to activate the receptor, determine the drug's effect on the tissue.
Drug-Receptor Interaction: Antagonist01:28

Drug-Receptor Interaction: Antagonist

An antagonist is a drug that binds strongly to a receptor without activating it. An antagonist prevents other molecules, such as neurotransmitters or hormones, from binding to the receptor and triggering a cellular response. Such interaction effectively hinders the normal physiological processes mediated by the receptor, resulting in various pharmacological effects depending on the specific receptor targeted.
Antagonists can be classified as competitive or noncompetitive based on their...
Adrenergic Receptors: ɑ Subtype01:31

Adrenergic Receptors: ɑ Subtype

Adrenoceptors are classified into α and ꞵ classes based on their potencies to catecholamine agonists. α-adrenoceptors show the following order of catecholamine potency:
Adrenaline ≥ Noradrenaline >> Isoprenaline
α-adrenoceptors are further divided into α1 and α2-adrenoceptors.
α1-Adrenoceptors: These receptors are located postsynaptically on the effector organs and cause constriction of smooth muscle mediated by activation of phospholipase C—inositol-1,4,5-trisphosphate...