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Molecular Pharmacology Fast Forward
First published on September 2, 2008; DOI: 10.1124/mol.108.050732

0026-895X/08/7406-1512-1520$20.00
Mol Pharmacol 74:1512-1520, 2008

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Structural Basis of Human Pregnane X Receptor Activation by the Hops Constituent Colupulone

Denise G. Teotico, Jason J. Bischof, Li Peng, Steven A. Kliewer, and Matthew R. Redinbo

Departments of Chemistry (D.G.T., J.J.B., M.R.R.) and Biochemistry and Biophysics (M.R.R.), University of North Carolina at Chapel Hill; and Departments of Molecular Biology and Pharmacology (L.P., S.A.K.), University of Texas Southwestern Medical Center, Dallas, Texas

Hops extracts are used to alleviate menopausal symptoms and as an alternative to hormone replacement therapy, but they can produce potentially harmful drug-drug interactions. The nuclear xenobiotic receptor pregnane X receptor (PXR) is promiscuously activated by a range of structurally distinct chemicals. It has a key role in the transcriptional regulation of genes that encode xenobiotic metabolism enzymes. In this study, hops extracts are shown to induce the expression of numerous drug metabolism and excretion proteins. The β-bitter acid colupulone is demonstrated to be a bioactive component and direct activator of human PXR. The 2.8-Å resolution crystal structure of the ligand binding domain of human PXR in complex with colupulone was elucidated, and colupulone was observed to bind in a single orientation stabilized by both van der Waals and hydrogen bonding contacts. The crystal structure also indicates that related {alpha}- and β-bitter acids have the capacity to serve as PXR agonists as well. Taken together, these results reveal the structural basis for drug-drug interactions mediated by colupulone and related constituents of hops extracts.

Received July 17, 2008; accepted September 2, 2008

Address correspondence to: Dr. Matthew R. Redinbo, Department of Chemistry, Campus Box 3290, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-3290. E-mail: redinbo{at}unc.edu






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