2.1 Å Crystal Structure of Human PXR in Complex with the St. John's Wort Compound Hyperforin
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- 作者：Ryan E. Watkins ; Jodi M. Maglich ; Linda B. Moore ; G. Bruce Wisely ; Schroeder M. Noble ; Paula R. Davis-Searles ; Mill H. Lambert ; Steven A. Kliewer ; and Matthew R. Redinbo
- 刊名：Biochemistry
- 出版年：2003
- 出版时间：February 18, 2003
- 年：2003
- 卷：42
- 期：6
- 页码：1430 - 1438
- 全文大小：664K
- 年卷期：v.42,no.6(February 18, 2003)
- ISSN：1520-4995
文摘
The nuclear xenobiotic receptor PXR is activated by a wide variety of clinically used drugsand serves as a master regulator of drug metabolism and excretion gene expression in mammals. St.John's wort is used widely in Europe and the United States to treat depression. This unregulated herbalremedy leads to dangerous drug-drug interactions, however, in patients taking oral contraceptives,antivirals, or immunosuppressants. Such interactions are caused by the activation of the human PXR byhyperforin, the psychoactive agent in St. John's wort. In this study, we show that hyperforin induces theexpression of numerous drug metabolism and excretion genes in primary human hepatocytes. We presentthe 2.1 Å crystal structure of hyperforin in complex with the ligand binding domain of human PXR.Hyperforin induces conformational changes in PXR's ligand binding pocket relative to structures of humanPXR elucidated previously and increases the size of the pocket by 250 Å3. We find that the mutation ofindividual aromatic residues within the ligand binding cavity changes PXR's response to particular ligands.Taken together, these results demonstrate that PXR employs structural flexibility to expand the chemicalspace it samples and that the mutation of specific residues within the ligand binding pocket of PXR tunesthe receptor's response to ligands.