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| Matt Redinbo, associate professor of chemistry at UNC Chapel Hill, and biochemistry PhD student, Ryan Watkins, are studying the structure of the Pregnane X receptor (PXR) in humans. PXR binds to different foreign compounds in the liver and signals that they should be collected and disposed of. It is therefore extremely important in analyzing human response to drugs. |
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| PXR has recently made medical news in connection with "miracle babies" born to women who were simultaneously taking birth control pills and an over-the-counter herbal remedy, St. Johns wort. An article in Lancet in Feb 2000 pointed out this correlation, and a study in June 2000 indicated that the reason was that St. John's wort was stimulating PXR, which was causing the birth control drugs to be broken down faster, and limiting their effectiveness. The FDA issued a Public Health Advisory that states that "St John's wort appears to be an inducer of the metabolic pathway cytochrome P450... Because many drugs that are used to treat heart disease, seizures, certain cancers, or to prevent transplant rejection or pregnancy are metabolized through this pathway, health care providers should alert patients about these potential drug interactions." http://jama.ama-assn.org/issues/v283n13/ffull/jfd00002-1.html | |
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| Snoeyink, Kettner, Berretty, and Mascarenhas (UNC Computer Science) are working with Redinbo and Watkins to analyze the specificity of PXR binding for both human and mouse. Under our current hypothesis, this is predominantly a geometric matching problem: The binding pocket in PXR appears to be unusually large, smooth and uniformly hydrophobic, so hydrogen bonding and steric interactions are conjectured to dominate the protein/ligand interactions. |
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References: Jobst KA and others. Safety of St John's wort. Lancet 355:576, 2000. Moore LB, Goodwin B, Jones SA, Wisely GB, Serabjit-Singh CJ, Willson TM, Collins JL, Kliewer SA. St. John's wort induces hepatic drug metabolism through activation of the pregnane X receptor. Proc Natl Acad Sci U S A. 2000 Jun 20;97(13):7500-2. Watkins
RE, Wisely GB, Moore LB, Collins JL, Lambert MH, Williams SP, Wilson TM,
Kliewer SA, Redinbo MR. The Human Nuclear Xenobiotic Receptor PXR: Structural
Determinants of Directed Promiscuity. Science 2001 Jun 22; 292 (5525):
2329-2333. |