Le Guével Rémy, Oger Frédérik, Martinez-Jimenez Celia P, Bizot Maud, Gheeraert Céline, Firmin François, Ploton Maheul, Kretova Miroslava, Palierne Gaëlle, Staels Bart, Barath Peter, Talianidis Iannis, Lefebvre Philippe, Eeckhoute Jérôme, Salbert Gilles
Université Rennes 1 , F-35042 Rennes, France.
UMR6290 CNRS, Team SP@RTE, Campus de Beaulieu, F-35042 Rennes, France.
ACS Chem Biol. 2017 Mar 17;12(3):654-663. doi: 10.1021/acschembio.6b00593. Epub 2017 Jan 13.
Chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII/NR2F2) is an orphan member of the nuclear receptor family of transcription factors whose activities are modulated upon binding of small molecules into an hydrophobic ligand-binding pocket (LBP). Although the LBP of COUP-TFII is filled with aromatic amino-acid side chains, alternative modes of ligand binding could potentially lead to regulation of the orphan receptor. Here, we screened a synthetic and natural compound library in a yeast one-hybrid assay and identified 4-methoxynaphthol as an inhibitor of COUP-TFII. This synthetic inhibitor was able to counteract processes either positively or negatively regulated by COUP-TFII in different mammalian cell systems. Hence, we demonstrate that the true orphan receptor COUP-TFII can be targeted by small chemicals which could be used to study the physiological functions of COUP-TFII or to counteract detrimental COUP-TFII activities in various pathological conditions.
鸡卵清蛋白上游启动子转录因子II（COUP - TFII/NR2F2）是核受体转录因子家族的一个孤儿成员，其活性在小分子结合到疏水配体结合口袋（LBP）时受到调节。尽管COUP - TFII的LBP充满了芳香族氨基酸侧链，但配体结合的替代模式可能潜在地导致该孤儿受体的调节。在这里，我们在酵母单杂交试验中筛选了一个合成和天然化合物库，并鉴定出4 - 甲氧基萘酚是COUP - TFII的一种抑制剂。这种合成抑制剂能够在不同的哺乳动物细胞系统中抵消由COUP - TFII正向或负向调节的过程。因此，我们证明真正的孤儿受体COUP - TFII可以被小分子靶向，这些小分子可用于研究COUP - TFII的生理功能或在各种病理条件下抵消有害的COUP - TFII活性。
