@article{39bc4966749c4f96ba89d7da2efb08d1,
title = "A structural basis for constitutive activity in the human CAR/RXRα heterodimer",
abstract = "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.",
author = "Xu, {Robert X.} and Lambert, {Millard H.} and Wisely, {Bruce B.} and Warren, {Erin N.} and Weinert, {Emily E.} and Waitt, {Gregory M.} and Williams, {Jon D.} and Collins, {Jon L.} and Moore, {Linda B.} and Willson, {Timothy M.} and Moore, {John T.}",
note = "Funding Information: We thank Robert T. Nolte, Shawn P. Williams, Lisa M. Shewchuk, and Lee F. Kuyper for useful discussion and advice; Robert T. Gampe and Valerie Montana for technical support; Steven J. Ratcliffe for synthesizing the SRC-1 peptide; and Drake S. Eggleston for encouragement and support. Data were collected at beamline 17-ID in the facilities of the Industrial Macromolecular Crystallography Association Collaborative Access Team at the Advanced Photon Source. These facilities are supported by the companies of the Industrial Macromolecular Crystallography Association through a contract with Illinois Institute of Technology (IIT) and executed through IIT's Center for Synchrotron Radiation Research and Instrumentation. Use of the Advanced Photon Source was supported by the U.S. Department of Energy, Basic Energy Sciences, Office of Science under contract number W-31-109-Eng-38. ",
year = "2004",
month = dec,
day = "22",
doi = "10.1016/j.molcel.2004.11.042",
language = "English (US)",
volume = "16",
pages = "919--928",
journal = "Molecular cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "6",
}