2.1 A crystal structure of human PXR in complex with the St. John's wort compound hyperforin

Biochemistry. 2003 Feb 18;42(6):1430-8. doi: 10.1021/bi0268753.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antidepressive Agents / chemistry*
  • Antidepressive Agents / pharmacology
  • Binding Sites / genetics
  • Biopolymers / chemistry
  • Biopolymers / genetics
  • Bridged Bicyclo Compounds
  • Cell Line
  • Cells, Cultured
  • Chlorocebus aethiops
  • Computer Simulation
  • Crystallization
  • Crystallography, X-Ray
  • Cytochrome P-450 Enzyme System / genetics
  • Gene Expression Regulation / drug effects
  • Humans
  • Hypericum / chemistry*
  • Ligands
  • Models, Molecular
  • Mutagenesis, Site-Directed
  • Phloroglucinol / analogs & derivatives
  • Pregnane X Receptor
  • Protein Binding / genetics
  • Protein Structure, Tertiary / genetics
  • Receptors, Cytoplasmic and Nuclear / chemistry*
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Steroid / chemistry*
  • Receptors, Steroid / genetics
  • Structure-Activity Relationship
  • Terpenes / chemistry*
  • Terpenes / pharmacology
  • Transfection


  • Antidepressive Agents
  • Biopolymers
  • Bridged Bicyclo Compounds
  • Ligands
  • Pregnane X Receptor
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Steroid
  • Terpenes
  • Cytochrome P-450 Enzyme System
  • Phloroglucinol
  • hyperforin

Associated data

  • PDB/1M13