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Identification of a novel FXR ligand that regulates metabolism
Structural highlights
FunctionNCOR1_HUMAN Mediates transcriptional repression by certain nuclear receptors. Part of a complex which promotes histone deacetylation and the formation of repressive chromatin structures which may impede the access of basal transcription factors.[1] Publication Abstract from PubMedFarnesoid 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. The antiparasitic drug ivermectin is a novel FXR ligand that regulates metabolism.,Jin L, Feng X, Rong H, Pan Z, Inaba Y, Qiu L, Zheng W, Lin S, Wang R, Wang Z, Wang S, Liu H, Li S, Xie W, Li Y Nat Commun. 2013;4:1937. doi: 10.1038/ncomms2924. PMID:23728580[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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