@article{292502793ace4af89ba49e697871401d,
title = "Differential Modulation of Nuclear Receptor LRH-1 through Targeting Buried and Surface Regions of the Binding Pocket",
abstract = "Liver receptor homologue-1 (LRH-1) is a phospholipid-sensing nuclear receptor that has shown promise as a target for alleviating intestinal inflammation and metabolic dysregulation in the liver. LRH-1 contains a large ligand-binding pocket, but generating synthetic modulators has been challenging. We have had recent success generating potent and efficacious agonists through two distinct strategies. We targeted residues deep within the pocket to enhance compound binding and residues at the mouth of the pocket to mimic interactions made by phospholipids. Here, we unite these two designs into one molecule to synthesize the most potent LRH-1 agonist to date. Through a combination of global transcriptomic, biochemical, and structural studies, we show that selective modulation can be driven through contacting deep versus surface polar regions in the pocket. While deep pocket contacts convey high affinity, contacts with the pocket mouth dominate allostery and provide a phospholipid-like transcriptional response in cultured cells.",
author = "Cato, {Michael L.} and Cornelison, {Jeffery L.} and Spurlin, {Racheal M.} and Courouble, {Valentine V.} and Patel, {Anamika B.} and Flynn, {Autumn R.} and Johnson, {Alyssa M.} and Okafor, {C. Denise} and Filipp Frank and D'Agostino, {Emma H.} and Griffin, {Patrick R.} and Jui, {Nathan T.} and Ortlund, {Eric A.}",
note = "Funding Information: This work was supported by the National Institute of General Medical Sciences (Grant T32-GM008367 to M.L.C.), the National Institute of Diabetes and Digestive and Kidney Diseases (Grant F31DK122745 to M.L.C. and Grant R01-DK115213 to E.A.O. and N.T.J.), the National Science Foundation (Grant DGE-1444932 to E.H.D.), and the American Heart Association (Grant 20PRE35200311 to M.L.C.). Next-generation sequencing services were provided by the Yerkes NHP Genomics Core, which is supported in part by National Institutes of Health (NIH) Grant P51 OD011132. Sequencing data were acquired on an Illumina NovaSeq6000 funded by NIH Grant S10 OD026799. Publisher Copyright: {\textcopyright} 2022 American Chemical Society.",
year = "2022",
doi = "10.1021/acs.jmedchem.2c00235",
language = "English (US)",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
}