The nuclear xenobiotic receptor CAR: structural determinants of constitutive activation and heterodimerization.
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.
Suino
Kelly
K
Laboratory of Structural Sciences, Van Andel Research Institute, 333 Bostwick Avenue, Grand Rapids, MI 49503, USA.
Peng
Li
L
Reynolds
Ross
R
Li
Yong
Y
Cha
Ji-Young
JY
Repa
Joyce J
JJ
Kliewer
Steven A
SA
Xu
H Eric
HE
D000595:Amino Acid Sequence; D000818:Animals; D000090702:Constitutive Androstane Receptor; D018360:Crystallography, X-Ray; D019281:Dimerization; D008024:Ligands; D051379:Mice; D008969:Molecular Sequence Data; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry* / Q000302:isolation & purification / Q000378:metabolism; D047490:Retinoid X Receptor alpha / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism; D014157:Transcription Factors / Q000737:chemistry* / Q000302:isolation & purification / Q000378:metabolism
D000090702:Constitutive Androstane Receptor; D008024:Ligands; D018160:Receptors, Cytoplasmic and Nuclear; D047490:Retinoid X Receptor alpha; D014157:Transcription Factors