@article{551b04159b5043678254c206980e70ef,
title = "The nuclear xenobiotic receptor CAR: Structural determinants of constitutive activation and heterodimerization",
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.",
author = "Kelly Suino and Li Peng and Ross Reynolds and Yong Li and Cha, {Ji Young} and Repa, {Joyce J.} and Kliewer, {Steven A.} and Xu, {H. Eric}",
note = "Funding Information: We thank W.D. Tolbert and J.S. Brunzelle for assistance in data collection at sector 32 of the Advance Photo Source, J. Daugherty and T. Stanley for assistance with AlphaScreen assays, G. Cavey for mass spectrometry, D. Petillo for DNA sequencing, M. Lambert for TCPOBOP model and discussion, and W. Minor for the HKL2000 package. We also want to thank R. Yasmin and N. Noy for discussion of CAR/RXR heterodimerization. Use of the Advanced Photon Source was supported by the Office of Science of the U.S. Department of Energy. H.E.X. acknowledges a start-up funding from Van Andel Research Institute, the National Institutes of Health Nuclear Receptor Signaling Atlas orphan receptor program (U19DK62434-01), and the Michigan Economic Development Corporation and the Michigan Technology Tri-Corridor (Grant 085P1000817). S.A.K. and L.P. were supported by grants from the National Institutes of Health (DK62434) and the Robert A. Welch Foundation (I-1558), and J.Y.C. and J.J.R. were supported by an award from the American Heart Association, Texas Affiliate.",
year = "2004",
month = dec,
day = "22",
doi = "10.1016/j.molcel.2004.11.036",
language = "English (US)",
volume = "16",
pages = "893--905",
journal = "Molecular cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "6",
}