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Updated: Jul 6, 2026
10:51
Reverse Yeast Two-hybrid System to Identify Mammalian Nuclear Receptor Residues that Interact with Ligands and/or Antagonists
Published on: November 15, 2013
Evolution of pharmacologic specificity in the pregnane X receptor
Sean Ekins1, Erica J Reschly, Lee R Hagey
1Collaborations in Chemistry, Inc., Jenkintown, PA, USA. ekinssean@yahoo.com
BMC Evolutionary Biology
|April 4, 2008
Summary
Pregnane X receptor (PXR) ligand specificity varies greatly across species, with human, mouse, and rat PXRs sharing similar pharmacophores. The Western clawed frog PXR shows significant divergence in ligand selectivity.
Area of Science:
- Biochemistry
- Pharmacology
- Evolutionary Biology
Background:
- The pregnane X receptor (PXR) is a nuclear hormone receptor known for its high sequence diversity across species.
- Understanding PXR ligand activation is crucial for predicting drug metabolism and toxicity.
- Previous studies have highlighted PXR's role in xenobiotic metabolism but lacked cross-species pharmacophore comparisons.
Purpose of the Study:
- To determine the pharmacophores for activation of human, mouse, rat, rabbit, chicken, and zebrafish PXRs using a standardized set of 16 ligands.
- To compare the selectivity of human and zebrafish PXRs for steroidal compounds and xenobiotics.
- To investigate the ligand activation properties of Western clawed frog (Xenopus tropicalis) PXR and a sea squirt (Ciona intestinalis) VDR/PXR.
Main Methods:
- Pharmacophore analysis using a common set of 16 diverse ligands across multiple species.
- Comparative analysis of ligand selectivity between human and zebrafish PXRs.
- Cloning and functional characterization of PXR from Xenopus tropicalis and Ciona intestinalis.
Main Results:
- Human, mouse, and rat PXRs exhibit similar pharmacophores with large binding pockets, while zebrafish PXR has a constrained pocket.
- Chicken PXR displays a symmetrical pharmacophore with distinct features.
- Zebrafish PXR is activated by a subset of human PXR agonists; Ciona VDR/PXR prefers planar xenobiotics; Xenopus tropicalis PXR is activated only by benzoates.
Conclusions:
- PXR ligand specificity significantly differs across vertebrate and invertebrate species, unlike other nuclear hormone receptors.
- Shared pharmacophore features among human, mouse, and rat PXRs suggest functional overlap and conserved evolutionary pressures.
- The Western clawed frog PXR has significantly diverged in ligand selectivity compared to fish, bird, and mammalian PXRs.
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