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A Novel Class of Natural FXR Modulators with a Unique Mode of Selective Co‐regulator Assembly
Author(s) -
Zheng Weili,
Lu Yi,
Lin Shengchen,
Wang Rui,
Qiu Lin,
Zhu Yanlin,
Yao Benqiang,
Guo Fusheng,
Jin Shikai,
Jin Lihua,
Li Yong
Publication year - 2017
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201700059
Subject(s) - farnesoid x receptor , regulator , small molecule , chemistry , ligand (biochemistry) , biophysics , binding pocket , binding site , conformational change , hydrogen bond , nuclear receptor , computational biology , stereochemistry , biochemistry , molecule , receptor , biology , transcription factor , gene , organic chemistry
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.