RT Journal Article
SR Electronic
T1 Structural Basis of Human Pregnane X Receptor Activation by the Hops Constituent Colupulone
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 1512
OP 1520
DO 10.1124/mol.108.050732
VO 74
IS 6
A1 Denise G. Teotico
A1 Jason J. Bischof
A1 Li Peng
A1 Steven A. Kliewer
A1 Matthew R. Redinbo
YR 2008
UL http://molpharm.aspetjournals.org/content/74/6/1512.abstract
AB 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 α- 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. The American Society for Pharmacology and Experimental Therapeutics