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- W4366352190 abstract "Nuclear receptor liver receptor homolog-1 (LRH-1, NR5A2) is a lipid-regulated transcription factor and an important drug target for several liver diseases. Advances toward LRH-1 therapeutics have been driven recently by structural biology, with fewer contributions from compound screening. Standard LRH-1 screens detect compound-induced interaction between LRH-1 and a transcriptional coregulator peptide, an approach that excludes compounds that regulate LRH-1 through alternative mechanisms. Here, we developed a FRET-based LRH-1 screen that simply detects compound binding to LRH-1, applying it to discover 58 new compounds that bind the canonical ligand-binding site in LRH-1 (2.5% hit rate), also supported by computational docking. Four independent functional screens identified 15 of these 58 compounds to also regulate LRH-1 function in vitro or in living cells. Although one of these 15 compounds, abamectin, directly binds LRH-1 and regulates full-length LRH-1 in cells, abamectin failed to regulate the isolated ligand-binding domain in standard coregulator peptide recruitment assays using PGC1α, DAX-1, or SHP. Abamectin treatment of human liver HepG2 cells selectively regulated endogenous LRH-1 ChIP-seq target genes and pathways associated with known LRH-1 functions in bile acid and cholesterol metabolism. Thus, the screen reported here can discover compounds not likely to have been identified in standard LRH-1 compound screens but which bind and regulate full-length LRH-1 in cells." @default.
- W4366352190 created "2023-04-21" @default.
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- W4366352190 creator A5085188064 @default.
- W4366352190 date "2023-04-19" @default.
- W4366352190 modified "2023-10-17" @default.
- W4366352190 title "New High-Throughput Screen Discovers Novel Ligands of Full-Length Nuclear Receptor LRH-1" @default.
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- W4366352190 doi "https://doi.org/10.1021/acschembio.2c00805" @default.
- W4366352190 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/37074920" @default.
- W4366352190 hasPublicationYear "2023" @default.
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