title: The antiparasitic drug ivermectin is a novel FXR ligand that regulates metabolism.
abstract: Farnesoid X receptor (FXR) has important roles in maintaining bile acid and cholesterol homeostasis. Here we report that the antiparasitic drug ivermectin is a ligand for nuclear FXR. We identify ivermectin using a high-throughput compound library screening and show that it induces the transcriptional activity of the FXR with distinctive properties in modulating coregulator recruitment. The crystal structure of ivermectin complexed with the ligand-binding domain of FXR reveals a unique binding mode of ivermectin in the FXR ligand-binding pocket, including the highly dynamic AF-2 helix and an expanded ligand-binding pocket. Treatment of wild-type mice, but not of FXR-null mice, with ivermectin decreases serum glucose and cholesterol levels, suggesting that ivermectin regulates metabolism through FXR. Our results establish FXR as the first mammalian protein targeted by ivermectin with high selectivity. Considering that ivermectin is a widely used clinical drug, our findings reveal a safe template for the design of novel FXR ligands.
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Fujian 361005, China.
authors.forename: Lihua
authors.initials: L
authors.lastname: Jin
authors.forename: Xuhui
authors.initials: X
authors.lastname: Feng
authors.forename: Hui
authors.initials: H
authors.lastname: Rong
authors.forename: Zhifu
authors.initials: Z
authors.lastname: Pan
authors.forename: Yuka
authors.initials: Y
authors.lastname: Inaba
authors.forename: Lin
authors.initials: L
authors.lastname: Qiu
authors.forename: Weili
authors.initials: W
authors.lastname: Zheng
authors.forename: Shengchen
authors.initials: S
authors.lastname: Lin
authors.forename: Rui
authors.initials: R
authors.lastname: Wang
authors.forename: Zhao
authors.initials: Z
authors.lastname: Wang
authors.forename: Shanshan
authors.initials: S
authors.lastname: Wang
authors.forename: Hongyan
authors.initials: H
authors.lastname: Liu
authors.forename: Song
authors.initials: S
authors.lastname: Li
authors.forename: Wen
authors.initials: W
authors.lastname: Xie
authors.forename: Yong
authors.initials: Y
authors.lastname: Li
mesh_terms: D000818:Animals; D000977:Antiparasitic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D019556:COS Cells; D002522:Chlorocebus aethiops; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000188:drug therapy / Q000378:metabolism; D059305:Diet, High-Fat; D006801:Humans; D006943:Hyperglycemia / Q000150:complications / Q000188:drug therapy / Q000378:metabolism; D006949:Hyperlipidemias / Q000150:complications / Q000188:drug therapy / Q000378:metabolism; D007559:Ivermectin / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D008024:Ligands; D008660:Metabolism / Q000187:drug effects*; D051379:Mice; D018345:Mice, Knockout; D008958:Models, Molecular; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry / Q000378:metabolism*; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D000977:Antiparasitic Agents; D007559:Ivermectin; D008024:Ligands; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated