title: A Novel Class of Natural FXR Modulators with a Unique Mode of Selective Co-regulator Assembly.
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.
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Innovation Center for Cell Signaling Network, Xiamen University, Xiamen, Fujian, 361005, China.
authors.forename: Weili
authors.initials: W
authors.lastname: Zheng
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Innovation Center for Cell Signaling Network, Xiamen University, Xiamen, Fujian, 361005, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Lu
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Innovation Center for Cell Signaling Network, Xiamen University, Xiamen, Fujian, 361005, China.
authors.forename: Shengchen
authors.initials: S
authors.lastname: Lin
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Innovation Center for Cell Signaling Network, Xiamen University, Xiamen, Fujian, 361005, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Innovation Center for Cell Signaling Network, Xiamen University, Xiamen, Fujian, 361005, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Qiu
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Innovation Center for Cell Signaling Network, Xiamen University, Xiamen, Fujian, 361005, China.
authors.forename: Yanlin
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Innovation Center for Cell Signaling Network, Xiamen University, Xiamen, Fujian, 361005, China.
authors.forename: Benqiang
authors.initials: B
authors.lastname: Yao
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Innovation Center for Cell Signaling Network, Xiamen University, Xiamen, Fujian, 361005, China.
authors.forename: Fusheng
authors.initials: F
authors.lastname: Guo
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Innovation Center for Cell Signaling Network, Xiamen University, Xiamen, Fujian, 361005, China.
authors.forename: Shikai
authors.initials: S
authors.lastname: Jin
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Innovation Center for Cell Signaling Network, Xiamen University, Xiamen, Fujian, 361005, China.
authors.forename: Lihua
authors.initials: L
authors.lastname: Jin
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Innovation Center for Cell Signaling Network, Xiamen University, Xiamen, Fujian, 361005, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Li
mesh_terms: D000818:Animals; D001665:Binding Sites; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology*; D043822:Cyclodecanes / Q000494:pharmacology*; D000882:Haplorhini; D056945:Hep G2 Cells; D006801:Humans; D062385:Hydroxybenzoates / Q000494:pharmacology*; D019410:Interleukin-16 / Q000378:metabolism; D008024:Ligands; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010226:Parabens / Q000494:pharmacology*; D017354:Point Mutation; D017434:Protein Structure, Tertiary; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000737:chemistry / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D001643:Bridged Bicyclo Compounds; D043822:Cyclodecanes; D062385:Hydroxybenzoates; D019410:Interleukin-16; D008024:Ligands; D052247:Nitric Oxide Synthase Type II; D010226:Parabens; D018160:Receptors, Cytoplasmic and Nuclear; D014409:Tumor Necrosis Factor-alpha; D000099150:Receptor, Farnesoid X-Activated; C000622615:feroline; C449651:tschimgin; C496319:NOS2 protein, human
keywords: co-regulator assembly; drug discovery; natural products; nuclear receptor FXR; structure-activity relationships