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Submitted on August 8, 2006
Accepted on February 19, 2007
Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599; Molecular Discovery Research, GlaxoSmithKline, Research Triangle Park, NC 27709; Department of Molecular Biology, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390; Department of Biochemistry and Biophysics, and the Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599
* To whom correspondence should be addressed. E-mail: redinbo{at}unc.edu.
The human nuclear pregnane X receptor (PXR) responds to a wide variety of xenobiotic and endobiotic compounds, including pregnanes, progesterones, corticosterones, lithocholic acids, and 17
-estradiol. In response to these ligands, the receptor controls the expression of genes central to the metabolism and excretion of potentially harmful chemicals from both exogenous and endogenous sources. While the structural basis of PXR's interaction with small and large xenobiotics has been examined, the detailed nature of its binding to endobiotics, including steroid-like ligands, remains unclear. We report the crystal structure of the human PXR ligand binding domain (LBD) in complex with 17-estradiol, a representative steroid ligand, at 2.65 Å resolution. Estradiol is found to occupy only one region of PXR's expansive ligand binding pocket, leaving a notable 1,000 Å3 of space unoccupied, and to bridge between the key polar residues Ser-247 and Arg-410 in the PXR LBD. Positioning the steroid scaffold in this way allows it to make several direct contacts to 
AF of the receptor's AF-2 region. The PXR-estradiol complex was compared to that of other nuclear receptors, including the estrogen receptor, in complexes with analogous ligands. It was found that PXR's placement of the steroid is remarkably distinct relative to other members of the nuclear receptor superfamily. Using the PXR-estradiol complex as a guide, the binding of other steroid- and cholesterol-like molecules was then considered. The results provide detailed insights into the manner in which human PXR responds to a wide range of endobiotic compounds.
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