The nuclear xenobiotic receptor CAR: structural determinants of constitutive activation and heterodimerization

Mol Cell. 2004 Dec 22;16(6):893-905. doi: 10.1016/j.molcel.2004.11.036.

Abstract

Constitutive androstane receptor (CAR) induces xenobiotic, bilirubin, and thyroid hormone metabolism as a heterodimer with the retinoid X receptor (RXR). Unlike ligand-dependent nuclear receptors, CAR is constitutively active. Here, we report the heterodimeric structure of the CAR and RXR ligand binding domains (LBDs), which reveals an unusually large dimerization interface and a small CAR ligand binding pocket. Constitutive CAR activity appears to be mediated by the compact nature of the CAR LBD that displays several unique features including a shortened AF2 helix and helix H10, which are linked by a two-turn helix that normally adopts an extended loop in other receptors, and an extended helix H2 that stabilizes the canonical LBD fold by packing tightly against helix H3. These structural observations provide a molecular framework for understanding the atypical transcriptional activation properties of CAR.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Crystallography, X-Ray
  • Dimerization
  • Ligands
  • Mice
  • Molecular Sequence Data
  • Protein Binding
  • Protein Structure, Tertiary
  • Receptors, Cytoplasmic and Nuclear / chemistry*
  • Receptors, Cytoplasmic and Nuclear / isolation & purification
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Retinoid X Receptor alpha / chemistry
  • Retinoid X Receptor alpha / isolation & purification
  • Retinoid X Receptor alpha / metabolism
  • Transcription Factors / chemistry*
  • Transcription Factors / isolation & purification
  • Transcription Factors / metabolism

Substances

  • Ligands
  • Receptors, Cytoplasmic and Nuclear
  • Retinoid X Receptor alpha
  • Transcription Factors
  • constitutive androstane receptor

Associated data

  • PDB/1XLS