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| Investigators: Snoeyink; Hsu, Leaver-Fay, Mascarenhas, Redinbo, Watkins |
| 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. |
Year 2 Update: We have continued our study of the specificity of binding for the Pregnane X receptor (PXR) in humans. For a dozen ligands that have known binding affinities for human and mouse PXR, we have explored the hypothesis that this is predominantly a geometric matching problem: Redinbo and Watkins, who solved the structure of PXR, noted that the binding pocket in PXR appears to be unusually large, smooth, and uniformly hydrophobic, so conjectured that hydrogen bonding and steric hindrance dominate the protein/ligand interaction. We have analyzed all configurations that make a pair of hydrogen bonds, implemented a collision detection algorithm to test for steric hindrance, and called upon the Amber force field in the Ball library to score the resulting matches. It is difficult to validate the results of our algorithm until the crystallographers are able to determine more structures of PXR with bound ligands. What we currently do is test the most promising matches using a general program, AutoDock, to compare its relative scores of the configurations that we find. While the results look positive, we do not wish to stake too much on comparisons with another program. What we can say is that the study of PXR has been a valuable push to building a useful software library that incorporates geometric data structures and algorithms from CGAL, biochemical computations from Ball, and produces visualizations in RasMol.
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