A Novel Class of Natural FXR Modulators with a Unique Mode of Selective Co-regulator Assembly.

Weili Zheng, Yi Lu, Shengchen Lin, Rui Wang, Lin Qiu, Yanlin Zhu, Benqiang Yao, Fusheng Guo, Shikai Jin, Lihua Jin, Yong Li

Chembiochem : a European journal of chemical biology 2017 Apr 18

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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. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Citation

Weili Zheng, Yi Lu, Shengchen Lin, Rui Wang, Lin Qiu, Yanlin Zhu, Benqiang Yao, Fusheng Guo, Shikai Jin, Lihua Jin, Yong Li. A Novel Class of Natural FXR Modulators with a Unique Mode of Selective Co-regulator Assembly. Chembiochem : a European journal of chemical biology. 2017 Apr 18;18(8):721-725