A Novel Class of Natural FXR Modulators with a Unique Mode of Selective Co‐regulator Assembly. (15th March 2017)

• Record Type: Journal Article
• Authors: Zheng, Weili; Lu, Yi; Lin, Shengchen; Wang, Rui; Qiu, Lin; Zhu, Yanlin; Yao, Benqiang; Guo, Fusheng; Jin, Shikai; Jin, Lihua; Li, Yong
• Is Part Of: Chembiochem. Volume 18:Number 8(2017)
• Page Start: 721
• Page End: 725
• Publication Date: 2017-03-15
• Subjects: co-regulator assembly -- drug discovery -- natural products -- nuclear receptor FXR -- structure–activity relationships; Biochemistry -- Periodicals; Molecular biology -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1002/cbic.201700059
• Languages: English
• ISSNs: 1439-4227

Abstract

Abstract: 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 function 2 (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. Abstract : Feroline and tschimgine are novel modulators that bind FXR with a two‐pocket binding mode. They induce dynamic changes in the AF‐2 surface, thereby leading to differential co‐regulator profiling modulated by interactions unique to specific co‐regulators. This finding provides a new pharmacophore for drug‐design strategies for the regulation of FXR in the treatment of human diseases.