title: 2.1 A crystal structure of human PXR in complex with the St. John's wort compound hyperforin.
abstract: 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.
authors.affiliation: Department of Chemistry, The University of North Carolina at Chapel Hill, North Carolina 27599, USA.
authors.forename: Ryan E
authors.initials: RE
authors.lastname: Watkins
authors.forename: Jodi M
authors.initials: JM
authors.lastname: Maglich
authors.forename: Linda B
authors.initials: LB
authors.lastname: Moore
authors.forename: G Bruce
authors.initials: GB
authors.lastname: Wisely
authors.forename: Schroeder M
authors.initials: SM
authors.lastname: Noble
authors.forename: Paula R
authors.initials: PR
authors.lastname: Davis-Searles
authors.forename: Mill H
authors.initials: MH
authors.lastname: Lambert
authors.forename: Steven A
authors.initials: SA
authors.lastname: Kliewer
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Redinbo
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites / Q000235:genetics; D001704:Biopolymers / Q000737:chemistry / Q000235:genetics; D001643:Bridged Bicyclo Compounds; D002460:Cell Line; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D003198:Computer Simulation; D003460:Crystallization; D018360:Crystallography, X-Ray; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D020902:Hypericum / Q000737:chemistry*; D008024:Ligands; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D010696:Phloroglucinol / Q000031:analogs & derivatives; D000077297:Pregnane X Receptor; D011485:Protein Binding / Q000235:genetics; D017434:Protein Structure, Tertiary / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry* / Q000235:genetics; D011987:Receptors, Steroid / Q000737:chemistry* / Q000235:genetics; D013329:Structure-Activity Relationship; D013729:Terpenes / Q000737:chemistry* / Q000494:pharmacology; D014162:Transfection
chemical_list: D000928:Antidepressive Agents; D001704:Biopolymers; D001643:Bridged Bicyclo Compounds; D008024:Ligands; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D013729:Terpenes; D003577:Cytochrome P-450 Enzyme System; D010696:Phloroglucinol; C001654:hyperforin