A structural basis for constitutive activity in the human CAR/RXRα heterodimer

Robert X. Xu, Millard H. Lambert, Bruce B. Wisely, Erin N. Warren, Emily E. Weinert, Gregory M. Waitt, Jon D. Williams, Jon L. Collins, Linda B. Moore, Timothy M. Willson, John T. Moore

Research output: Contribution to journalArticlepeer-review

205 Scopus citations


The X-ray crystal structure of the human constitutive androstane receptor (CAR, NR1I3)/retinoid X receptor α (RXRα, NR2B1) heterodimer sheds light on the mechanism of ligand-independent activation of transcription by nuclear receptors. CAR contains a single-turn Helix X that restricts the conformational freedom of the C-terminal AF2 helix, favoring the active state of the receptor. Helix X and AF2 sit atop four amino acids that shield the CAR ligand binding pocket. A fatty acid ligand was identified in the RXRα binding pocket. The endogenous RXRα ligand, combined with stabilizing interactions from the heterodimer interface, served to hold RXRα in an active conformation. The structure suggests that upon translocation, CAR/RXRα heterodimers are preorganized in an active conformation in cells such that they can regulate transcription of target genes. Insights into the molecular basis of CAR constitutive activity can be exploited in the design of inverse agonists as drugs for treatment of obesity.

Original languageEnglish (US)
Pages (from-to)919-928
Number of pages10
JournalMolecular cell
Issue number6
StatePublished - Dec 22 2004

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology


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