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Updated: Aug 23, 2025

Reverse Yeast Two-hybrid System to Identify Mammalian Nuclear Receptor Residues that Interact with Ligands and/or Antagonists
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Reverse Yeast Two-hybrid System to Identify Mammalian Nuclear Receptor Residues that Interact with Ligands and/or Antagonists

Published on: November 15, 2013

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Mechanistic Impact of Different Ligand Scaffolds on FXR Modulation Suggests Avenues to Selective Modulators

Jan Heering1, Nathalie Jores2, Whitney Kilu3

  • 1Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, and Fraunhofer Cluster of Excellence for Immune Mediated Diseases CIMD, 60596Frankfurt, Germany.

ACS Chemical Biology
|November 1, 2022
PubMed

Insights

Selective modulation of the farnesoid X receptor (FXR) offers potential for treating liver and metabolic diseases. Different ligands impact FXR activity by altering dimerization and co-regulator interactions, paving the way for targeted therapies.

Area of Science:

  • Molecular endocrinology
  • Drug discovery and development
  • Metabolic disease research

Background:

  • The nuclear farnesoid X receptor (FXR) is a key regulator of bile acid homeostasis and a therapeutic target for hepatic and metabolic diseases.
  • Clinical applications of FXR activators are limited by adverse effects, necessitating a deeper understanding of their molecular mechanisms.
  • FXR plays a crucial role in regulating genes involved in lipid, glucose, and bile acid metabolism.

Purpose of the Study:

  • To elucidate the molecular mechanisms underlying farnesoid X receptor (FXR) activation by diverse ligands.
  • To investigate the impact of different FXR ligands on FXR co-regulator interactions and dimerization.
  • To explore the potential for designing selective FXR modulators for therapeutic benefit.

Main Methods:

  • Systematic study of FXR co-regulator interactions and dimerization in response to seven chemically diverse FXR ligands.
  • Analysis of molecular effects on FXR activation correlated with structural changes in the FXR ligand-binding domain.
  • Assessment of gene expression patterns regulated by FXR activation and partial agonism.

Main Results:

  • Distinct molecular effects on FXR activation were observed for different ligand scaffolds, correlating with structural changes in the FXR ligand-binding domain.
  • A partial FXR agonist primarily induced co-repressor displacement, leading to a unique FXR-regulated gene expression profile compared to full agonists.
  • Ligand-dependent modulation of FXR dimerization and co-regulator interactions was evident.

Conclusions:

  • Selective modulation of FXR dimerization and co-regulator interactions by distinct ligands is achievable.
  • This selective modulation provides a promising strategy for developing gene- or tissue-selective FXR modulators.
  • Targeted FXR modulation could overcome limitations of current FXR-based therapies for hepatic and metabolic diseases.

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