Related Experiment Videos
A structural basis for constitutive activity in the human CAR/RXRalpha heterodimer
Robert X Xu1, Millard H Lambert, Bruce B Wisely
1Discovery Research, GlaxoSmithKline, Research Triangle Park, NC 27709, USA. robert.x.xu@gsk.com
Molecular Cell
|December 22, 2004
Summary
The crystal structure reveals how the constitutive androstane receptor (CAR) and retinoid X receptor alpha (RXRalpha) heterodimer is preorganized for ligand-independent transcription activation, offering insights for obesity drug design.
Area of Science:
- Molecular Biology
- Structural Biology
- Pharmacology
Background:
- Nuclear receptors like CAR (NR1I3) and RXRalpha (NR2B1) regulate gene transcription.
- Understanding ligand-independent activation mechanisms is crucial for therapeutic development.
Purpose of the Study:
- To elucidate the structural basis of the CAR/RXRalpha heterodimer's ligand-independent transcriptional activity.
- To identify potential targets for drug design related to CAR activity.
Main Methods:
- X-ray crystal structure determination of the human CAR/RXRalpha heterodimer.
- Analysis of receptor conformation and ligand interactions.
Main Results:
- Identified a unique Helix X in CAR that stabilizes an active conformation.
- Revealed a fatty acid ligand bound to RXRalpha, contributing to its active state.
- The CAR/RXRalpha heterodimer is preorganized in an active conformation for transcription.
Conclusions:
- The structure explains CAR's constitutive activity through conformational preorganization.
- Findings can inform the design of inverse agonists for obesity treatment targeting CAR.