Weili Zheng, Yi Lu, Shengchen Lin
Apr 18, 2017
Citations
1
Influential Citations
12
Citations
Journal
ChemBioChem
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.