1xv9 › Citations

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

Xu RX, Lambert MH, Wisely BB, Warren EN, Weinert EE, Waitt GM, Williams JD, Collins JL, Moore LB, Willson TM, Moore JT
Mol Cell 16 919-28 (2004)
Cited: 138 times
EuropePMC logo PMID: 15610735

Abstract

The X-ray crystal structure of the human constitutive androstane receptor (CAR, NR1I3)/retinoid X receptor alpha (RXRalpha, 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 RXRalpha binding pocket. The endogenous RXRalpha ligand, combined with stabilizing interactions from the heterodimer interface, served to hold RXRalpha in an active conformation. The structure suggests that upon translocation, CAR/RXRalpha 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.

Reviews - 1xv9 mentioned but not cited (6)

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Reviews citing this publication (44)

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Articles citing this publication (76)

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