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Ligand specificity of constitutive androstane receptor as probed by induced-fit docking and mutagenesis

Susanna Repo1, Johanna Jyrkkärinne, Juha T Pulkkinen

  • 1Structural Bioinformatics Laboratory, Department of Biochemistry and Pharmacy, Abo Akademi University, Tykistökatu 6, FI-20520 Turku, Finland.

Journal of Medicinal Chemistry
|November 1, 2008
PubMed

Insights

Constitutive androstane receptor (CAR) activity varies significantly between species due to differences in its ligand-binding pocket. Mutations reveal species-specific ligand responses, impacting drug metabolism and chemical sensing.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • The Constitutive androstane receptor (CAR, NR1I3) is a nuclear receptor crucial for sensing drugs and endogenous compounds.
  • CAR exhibits diverse ligand-binding preferences with significant interspecies variations.

Purpose of the Study:

  • To investigate the role of specific ligand-binding pocket (LBP) residues in mouse CAR (mCAR) activity.
  • To compare the functional differences of CAR residues between mouse and human CAR (hCAR).

Main Methods:

  • Site-directed mutagenesis of mCAR LBP residues.
  • Ligand-binding assays and activity measurements.
  • Molecular docking simulations.

Main Results:

  • Mutations in specific mCAR LBP residues (e.g., F171, Y336) differentially affected ligand activation.
  • Key CAR residues (e.g., N175, L253) demonstrated functionally distinct roles in mCAR versus hCAR.
  • Docking studies provided mechanistic insights into 17alpha-ethinyl-3,17beta-estradiol (EE2) mediated activation of mCAR and repression of hCAR.

Conclusions:

  • CAR's ligand specificity is highly dependent on species-specific amino acid residues within the LBP.
  • Understanding these species differences is critical for predicting drug responses and chemical sensing.
  • The study elucidates mechanisms underlying differential CAR activation/repression by specific ligands across species.

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