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Originally published in Science Express on 14 June 2001
Science 22 June 2001:
Vol. 292. no. 5525, pp. 2329 - 2333
DOI: 10.1126/science.1060762
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Reports

The Human Nuclear Xenobiotic Receptor PXR: Structural Determinants of Directed Promiscuity

Ryan E. Watkins,1 G. Bruce Wisely,3 Linda B. Moore,3 Jon L. Collins,3 Millard H. Lambert,3 Shawn P. Williams,3 Timothy M. Willson,3 Steven A. Kliewer,3 Matthew R. Redinbo2*

The human nuclear pregnane X receptor (hPXR) activates cytochrome P450-3A expression in response to a wide variety of xenobiotics and plays a critical role in mediating dangerous drug-drug interactions. We present the crystal structures of the ligand-binding domain of hPXR both alone and in complex with the cholesterol-lowering drug SR12813 at resolutions of 2.5 and 2.75 angstroms, respectively. The hydrophobic ligand-binding cavity of hPXR contains a small number of polar residues, permitting SR12813 to bind in three distinct orientations. The position and nature of these polar residues were found to be critical for establishing the precise pharmacologic activation profile of PXR. Our findings provide important insights into how hPXR detects xenobiotics and may prove useful in predicting and avoiding drug-drug interactions.

1 Department of Biochemistry and Biophysics, School of Medicine,
2 Department of Chemistry and Lineberger Comprehensive Cancer Center, University of North Carolina (UNC) at Chapel Hill, Chapel Hill, NC 27599, USA.
3 Nuclear Receptor Discovery Research, GlaxoSmithKline, Research Triangle Park, NC 27709, USA.
*   To whom correspondence should be addressed. E-mail: redinbo{at}unc.edu

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   Abstract »    Full Text »    PDF »
Alternatively spliced isoforms of the human constitutive androstane receptor.
S. S. Auerbach, R. Ramsden, M. A. Stoner, C. Verlinde, C. Hassett, and C. J. Omiecinski (2003)
Nucleic Acids Res. 31, 3194-3207
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Basis of a High-Throughput Method for Nuclear Receptor Ligands.
T. Kanayama, S. Mamiya, T. Nishihara, and J.-i. Nishikawa (2003)
J. Biochem. 133, 791-797
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Identification of a Novel Human Constitutive Androstane Receptor (CAR) Agonist and Its Use in the Identification of CAR Target Genes.
J. M. Maglich, D. J. Parks, L. B. Moore, J. L. Collins, B. Goodwin, A. N. Billin, C. A. Stoltz, S. A. Kliewer, M. H. Lambert, T. M. Willson, et al. (2003)
J. Biol. Chem. 278, 17277-17283
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Activation of Orphan Nuclear Constitutive Androstane Receptor Requires Subnuclear Targeting by Peroxisome Proliferator-activated Receptor gamma Coactivator-1alpha . A POSSIBLE LINK BETWEEN XENOBIOTIC RESPONSE AND NUTRITIONAL STATE.
T. Shiraki, N. Sakai, E. Kanaya, and H. Jingami (2003)
J. Biol. Chem. 278, 11344-11350
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The Critical Role of Carboxy-Terminal Amino Acids in Ligand-Dependent and -Independent Transactivation of the Constitutive Androstane Receptor.
T. Andersin, S. Vaisanen, and C. Carlberg (2003)
Mol. Endocrinol. 17, 234-246
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Molecular Basis for the Subtype Discrimination of the Estrogen Receptor-{beta}-Selective Ligand, Diarylpropionitrile.
J. Sun, J. Baudry, J. A. Katzenellenbogen, and B. S. Katzenellenbogen (2003)
Mol. Endocrinol. 17, 247-258
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Structural Biology of Bacterial Multidrug Resistance Gene Regulators.
M. H. Godsey, E. E. Zheleznova Heldwein, and R. G. Brennan (2002)
J. Biol. Chem. 277, 40169-40172
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The Nuclear Pregnane X Receptor: A Key Regulator of Xenobiotic Metabolism.
S. A. Kliewer, B. Goodwin, and T. M. Willson (2002)
Endocr. Rev. 23, 687-702
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Structurally and Functionally Important Amino Acids of the Agonistic Conformation of the Human Vitamin D Receptor.
S. Vaisanen, S. Ryhanen, J. T. A. Saarela, M. Perakyla, T. Andersin, and P. H. Maenpaa (2002)
Mol. Pharmacol. 62, 788-794
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Insights from a Three-Dimensional Model into Ligand Binding to Constitutive Active Receptor.
L. Xiao, X. Cui, V. Madison, R. E. White, and K.-C. Cheng (2002)
Drug Metab. Dispos. 30, 951-956
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Effects of Dexamethasone on Aryl (SULT1A1)- and Hydroxysteroid (SULT2A1)-Sulfotransferase Gene Expression in Primary Cultured Human Hepatocytes.
Z. Duanmu, D. Locke, J. Smigelski, W. Wu, M. S. Dahn, C. N. Falany, T. A. Kocarek, and M. Runge-Morris (2002)
Drug Metab. Dispos. 30, 997-1004
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A Structural Model of the Constitutive Androstane Receptor Defines Novel Interactions That Mediate Ligand-Independent Activity.
I. Dussault, M. Lin, K. Hollister, M. Fan, J. Termini, M. A. Sherman, and B. M. Forman (2002)
Mol. Cell. Biol. 22, 5270-5280
   Abstract »    Full Text »    PDF »
Minireview: Genomics Versus Orphan Nuclear Receptors--A Half-Time Report.
T. M. Willson and J. T. Moore (2002)
Mol. Endocrinol. 16, 1135-1144
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Determinants of the Substrate Specificity of Multidrug Resistance Protein 1. ROLE OF AMINO ACID RESIDUES WITH HYDROGEN BONDING POTENTIAL IN PREDICTED TRANSMEMBRANE HELIX 17.
D.-W. Zhang, S. P. C. Cole, and R. G. Deeley (2002)
J. Biol. Chem. 277, 20934-20941
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Pregnane X Receptor (PXR), Constitutive Androstane Receptor (CAR), and Benzoate X Receptor (BXR) Define Three Pharmacologically Distinct Classes of Nuclear Receptors.
L. B. Moore, J. M. Maglich, D. D. McKee, B. Wisely, T. M. Willson, S. A. Kliewer, M. H. Lambert, and J. T. Moore (2002)
Mol. Endocrinol. 16, 977-986
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Regulation of xenobiotic and bile acid metabolism by the nuclear pregnane X receptor.
S. A. Kliewer and T. M. Willson (2002)
J. Lipid Res. 43, 359-364
   Abstract »    Full Text »    PDF »
A Pharmacophore for Human Pregnane X Receptor Ligands.
S. Ekins and J. A. Erickson (2002)
Drug Metab. Dispos. 30, 96-99
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Structural Mechanisms of QacR Induction and Multidrug Recognition.
M. A. Schumacher, M. C. Miller, S. Grkovic, M. H. Brown, R. A. Skurray, and R. G. Brennan (2001)
Science 294, 2158-2163
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Natural Protein Variants of Pregnane X Receptor with Altered Transactivation Activity Toward CYP3A4.
E. Hustert, A. Zibat, E. Presecan-Siedel, R. Eiselt, R. Mueller, C. Fu{beta}, I. Brehm, U. Brinkmann, M. Eichelbaum, L. Wojnowski, et al. (2001)
Drug Metab. Dispos. 29, 1454-1459
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