期刊
CHEMBIOCHEM
卷 18, 期 8, 页码 721-725出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cbic.201700059
关键词
co-regulator assembly; drug discovery; natural products; nuclear receptor FXR; structure-activity relationships
资金
- National Basic Research Program of China (973 Program) [2012CB910104]
- National Natural Science Foundation of China [81273567, 81471084, U1405220, 31270776]
- Fundamental Research Funds for the Central Universities [20720150052]
- 111 Project of Ministry of Education of China [B06016]
- National Science Foundation of China for Fostering Talents in Basic Research [J1310027]
The farnesoid X receptor (FXR) is an important target for drug discovery. Small molecules induce a conformational change in FXR that modulates its binding to co-regulators, thus resulting in distinct FXR functional profiles. However, the mechanisms for selectively recruiting co-regulators by FXR remain elusive, partly because of the lack of FXR-selective modulators. We report the identification of two natural terpenoids, tschimgine and feroline, as novel FXR modulators. Remarkably, their crystal structures uncovered a secondary binding pocket important for ligand binding. Further, tschimgine or feroline induced dynamic conformational changes in the activation function2 (AF-2) surface, thus leading to differential co-regulator recruiting profiles, modulated by both hydrophobic and selective hydrogen-bond interactions unique to specific co-regulators. Our findings thus provide a novel structure template for optimization for FXR-selective modulators of clinical value.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据