6P2B

Tethered PXR-LBD/SRC-1p bound to Garcinoic Acid

6P2B の概要

• エントリーDOI: 10.2210/pdb6p2b/pdb
• 分子名称: Nuclear receptor subfamily 1 group I member 2, (2Z,6E,10E)-13-[(2R)-6-hydroxy-2,8-dimethyl-3,4-dihydro-2H-1-benzopyran-2-yl]-2,6,10-trimethyltrideca-2,6,10-trienoic acid, DIMETHYL SULFOXIDE, ... (4 entities in total)
• 機能のキーワード: garcinoic acid, nuclear receptor, transcription
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 79455.65

構造登録者

Walton, W.G.,Pellock, S.J.,Redinbo, M.R. (登録日: 2019-05-21, 公開日: 2020-04-01, 最終更新日: 2023-10-11)

主引用文献

Bartolini, D.,De Franco, F.,Torquato, P.,Marinelli, R.,Cerra, B.,Ronchetti, R.,Schon, A.,Fallarino, F.,De Luca, A.,Bellezza, G.,Ferri, I.,Sidoni, A.,Walton, W.G.,Pellock, S.J.,Redinbo, M.R.,Mani, S.,Pellicciari, R.,Gioiello, A.,Galli, F.
Garcinoic Acid Is a Natural and Selective Agonist of Pregnane X Receptor.
J.Med.Chem., 63:3701-3712, 2020

PubMed Abstract: Pregnane X receptor (PXR) is a master xenobiotic-sensing transcription factor and a validated target for immune and inflammatory diseases. The identification of chemical probes to investigate the therapeutic relevance of the receptor is still highly desired. In fact, currently available PXR ligands are not highly selective and can exhibit toxicity and/or potential off-target effects. In this study, we have identified garcinoic acid as a selective and efficient PXR agonist. The properties of this natural molecule as a specific PXR agonist were demonstrated by the screening on a panel of nuclear receptors, the assessment of the physical and thermodynamic binding affinity, and the determination of the PXR-garcinoic acid complex crystal structure. Cytotoxicity, transcriptional, and functional properties were investigated in human liver cells, and compound activity and target engagement were confirmed in vivo in mouse liver and gut tissue. In conclusion, garcinoic acid is a selective natural agonist of PXR and a promising lead compound toward the development of new PXR-regulating modulators.

PubMed: 32160459
DOI: 10.1021/acs.jmedchem.0c00012

実験手法

X-RAY DIFFRACTION (2.3 Å)