ArticleJournal of medicinal chemistry2022
Differential Modulation of Nuclear Receptor LRH-1 through Targeting Buried and Surface Regions of the Binding Pocket.
Article in Journal of medicinal chemistry, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
What it found
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The trial behind it
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Who cites it
8 citing papers in PubMed, 13 citations in OpenAlex.
- Microbiome-host communication via vaccenic acid modulates LRH-1/NR5A2 activity and ameliorates metabolic liver disease.EMBO molecular medicine · 2026Article
- From hepatic to hematopoietic: LRH-1's expanding cellular repertoire to the immune system.The FEBS journal · 2026Review
- Structure-guided compound prioritization strategy for virtual screening identifies putative binders for the nuclear receptor LRH-1.bioRxiv : the preprint server for biology · 2026Article
- Exploring the Expanding Role of Nuclear Receptor LRH-1/NR5A2 in Cell Biology and Immunity.International journal of cell biology · 2026Review
- A novel heuristic of rigid docking scores positively correlates with full-length nuclear receptor LRH-1 regulation.Computational and structural biotechnology journal · 2024Article
- Liver receptor homolog-1: structures, related diseases, and drug discovery.Acta pharmacologica Sinica · 2024Review
- Illuminating ligand-induced dynamics in nuclear receptors through MD simulations.Biochimica et biophysica acta. Gene regulatory mechanisms · 2024Review
- LRH-1 induces hepatoprotective nonessential amino acids in response to acute liver injury.The Journal of clinical investigation · 2023Article
Corrections and comments
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Authors and funding
13 authors at 2 institutions in 1 country.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.