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| {{STRUCTURE_1m13| PDB=1m13 | SCENE= }} | | {{STRUCTURE_1m13| PDB=1m13 | SCENE= }} |
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| '''Crystal Structure of the Human Pregane X Receptor Ligand Binding Domain in Complex with Hyperforin, a Constituent of St. John's Wort'''
| | ===Crystal Structure of the Human Pregane X Receptor Ligand Binding Domain in Complex with Hyperforin, a Constituent of St. John's Wort=== |
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| ==Overview==
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| The nuclear xenobiotic receptor PXR is activated by a wide variety of clinically used drugs and 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 herbal remedy 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 by hyperforin, the psychoactive agent in St. John's wort. In this study, we show that hyperforin induces the expression of numerous drug metabolism and excretion genes in primary human hepatocytes. We present the 2.1 A 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 human PXR elucidated previously and increases the size of the pocket by 250 A(3). We find that the mutation of individual 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 chemical space it samples and that the mutation of specific residues within the ligand binding pocket of PXR tunes the receptor's response to ligands. | | The line below this paragraph, {{ABSTRACT_PUBMED_12578355}}, adds the Publication Abstract to the page |
| | (as it appears on PubMed at http://www.pubmed.gov), where 12578355 is the PubMed ID number. |
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| | {{ABSTRACT_PUBMED_12578355}} |
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| ==About this Structure== | | ==About this Structure== |
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| [[Category: Nuclear receptor]] | | [[Category: Nuclear receptor]] |
| [[Category: Protein-ligand complex]] | | [[Category: Protein-ligand complex]] |
| ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 00:30:14 2008'' | | |
| | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jul 2 22:59:04 2008'' |
