1M13

Crystal Structure of the Human Pregane X Receptor Ligand Binding Domain in Complex with Hyperforin, a Constituent of St. John's Wort

Summary for 1M13

• Entry DOI: 10.2210/pdb1m13/pdb
• Related: 1ILG 1ILH
• Descriptor: Orphan Nuclear Receptor PXR, 4-HYDROXY-5-ISOBUTYRYL-6-METHYL-1,3,7-TRIS-(3-METHYL-BUT-2-ENYL)-6-(4-METHYL-PENT-3-ENYL)-BICYCLO[3.3.1]NON-3-ENE-2,9-DIONE (3 entities in total)
• Functional Keywords: nuclear receptor, ligand binding domain, protein-ligand complex, transcription
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus: O75469
• Total number of polymer chains: 1
• Total formula weight: 36817.65

Authors

Watkins, R.E.,Maglich, J.M.,Moore, L.B.,Wisely, G.B.,Noble, S.M.,Davis-Searles, P.R.,Lambert, M.H.,Kliewer, S.A.,Redinbo, M.R. (deposition date: 2002-06-17, release date: 2003-03-04, Last modification date: 2024-02-14)

Primary citation

Watkins, R.E.,Maglich, J.M.,Moore, L.B.,Wisely, G.B.,Noble, S.M.,Davis-Searles, P.R.,Lambert, M.H.,Kliewer, S.A.,Redinbo, M.R.
2.1 A Crystal Structure of Human PXR in Complex with the St. John's Wort Compound Hyperforin
Biochemistry, 42:1430-1438, 2003

PubMed 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.

PubMed: 12578355
DOI: 10.1021/bi0268753

Experimental method

X-RAY DIFFRACTION (2.15 Å)