Structural basis of human pregnane X receptor activation by the hops constituent colupulone

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

Research output: Contribution to journalArticle

49 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1512-1520
Number of pages9
JournalMolecular Pharmacology
Volume74
Issue number6
DOIs
StatePublished - Dec 1 2008

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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