1m13
From Proteopedia
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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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[[Category: Watkins, R E.]] | [[Category: Watkins, R E.]] | ||
[[Category: Wisely, G B.]] | [[Category: Wisely, G B.]] | ||
| - | [[Category: | + | [[Category: Ligand binding domain]] |
| - | [[Category: | + | [[Category: Nuclear receptor]] |
| - | [[Category: | + | [[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 | + | |
Revision as of 21:30, 2 May 2008
Crystal Structure of the Human Pregane X Receptor Ligand Binding Domain in Complex with Hyperforin, a Constituent of St. John's Wort
Overview
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.
About this Structure
1M13 is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
2.1 A crystal structure of human PXR in complex with the St. John's wort compound hyperforin., Watkins RE, Maglich JM, Moore LB, Wisely GB, Noble SM, Davis-Searles PR, Lambert MH, Kliewer SA, Redinbo MR, Biochemistry. 2003 Feb 18;42(6):1430-8. PMID:12578355 Page seeded by OCA on Sat May 3 00:30:14 2008
