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Molecular dynamics simulations for human CAR inverse agonists.

Johanna Jyrkkärinne1, Jenni Küblbeck, Juha Pulkkinen

  • 1School of Pharmacy, University of Eastern Finland, Faculty of Health Sciences, P.O. Box 1627, FI-70211 Kuopio, Finland. Johanna.Jyrkkärinne@uef.fi

Journal of Chemical Information and Modeling
|January 12, 2012
PubMed
Summary

Constitutive androstane receptor (CAR) structural dynamics were investigated. A corepressor peptide induced a clear shift in CAR's helix 12 when bound to inverse agonists, revealing new insights into CAR regulation.

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Structural Biology

Background:

  • Constitutive androstane receptor (CAR) and pregnane x receptor (PXR) are key hepatocyte metabolic sensors.
  • Nuclear receptors (NRs) interact with coactivators and corepressors, with helix 12 (H12) position dictating interaction type.
  • CAR exhibits constitutive activity, modulated by ligands, but structural data with inverse agonists and corepressors were lacking.

Purpose of the Study:

  • To investigate the structural dynamics of human CAR, specifically the movement of H12.
  • To understand how inverse agonists and corepressors influence CAR conformation.
  • To elucidate the mechanism of CAR repression by inverse agonists.

Main Methods:

  • Molecular dynamics (MD) simulations were employed.
  • Simulations included activating and repressing ligands alongside a corepressor peptide.
  • Analysis focused on the conformational changes of CAR's H12.

Main Results:

  • The presence of a corepressor peptide induced a distinct shift in H12 of inverse agonist-bound CAR.
  • H12 moved towards H10, unlike in some other NRs.
  • CAR's short H12 conformation was sufficient to accommodate corepressor binding.

Conclusions:

  • CAR's H12 undergoes significant movement upon corepressor binding, even with inverse agonists.
  • This finding provides crucial structural insights into CAR-mediated repression.
  • The study clarifies the mechanism by which CAR is regulated by different ligands and coregulators.