1M13

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

1M13 の概要

• エントリーDOI: 10.2210/pdb1m13/pdb
• 関連するPDBエントリー: 1ILG 1ILH
• 分子名称: 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)
• 機能のキーワード: nuclear receptor, ligand binding domain, protein-ligand complex, transcription
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Nucleus: O75469
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 36817.65

構造登録者

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. (登録日: 2002-06-17, 公開日: 2003-03-04, 最終更新日: 2024-02-14)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.15 Å)