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Reverse Yeast Two-hybrid System to Identify Mammalian Nuclear Receptor Residues that Interact with Ligands and/or Antagonists
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Recognition of LXXLL by ligand binding domain of the Farnesoid X receptor in molecular dynamics simulation

Tao Zhang1, Xi-Cheng Dong, Min-Bo Chen

  • 1Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, P. R. China, 200032.

Journal of Chemical Information and Modeling
|November 28, 2006
PubMed

Insights

Farnesoid X receptor (FXR) interactions with coactivator proteins were simulated. Molecular dynamics revealed key hydrophobic and hydrogen bonding interactions, supporting the

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Structural Biology

Background:

  • The Farnesoid X receptor (FXR) is a nuclear receptor and a potential therapeutic target.
  • Coactivator recruitment via the LXXLL motif is crucial for nuclear receptor transcriptional activation.

Purpose of the Study:

  • To investigate the molecular interactions between the FXR ligand-binding domain (LBD) and coactivator proteins.
  • To provide molecular insights into the initial steps of FXR transcriptional activation.

Main Methods:

  • A 25 ns molecular dynamics simulation was employed to observe the recognition process.
  • Analysis of hydrophobic and hydrogen bonding interactions between FXR LBD and coactivator peptide.

Main Results:

  • Detailed analysis of hydrophobic and hydrogen bonding interactions during coactivator binding.
  • Simulation data supports the proposed 'on deck' model for coactivator recruitment.
  • Identified key protein-polypeptide interactions and conformational changes.

Conclusions:

  • The study elucidates the molecular basis of LXXLL motif recognition by FXR LBD.
  • Findings support the 'on deck' model, offering a mechanistic understanding of FXR activation.
  • Provides insights into protein-polypeptide interactions relevant for FXR-targeted drug design.

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