ArticleThe Journal of biological chemistry2016
Unexpected Allosteric Network Contributes to LRH-1 Co-regulator Selectivity.
Article in The Journal of biological chemistry, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 31 citations in OpenAlex.
- 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
- International Union of Basic and Clinical Pharmacology CXIII: Nuclear Receptor Superfamily-Update 2023.Pharmacological reviews · 2023Review
- The nuclear receptor LRH-1 discriminates between ligands using distinct allosteric signaling circuits.Protein science : a publication of the Protein Society · 2023Article
- New High-Throughput Screen Discovers Novel Ligands of Full-Length Nuclear Receptor LRH-1.ACS chemical biology · 2023Article
- A phospholipid mimetic targeting LRH-1 ameliorates colitis.Cell chemical biology · 2022Article
- Differential Modulation of Nuclear Receptor LRH-1 through Targeting Buried and Surface Regions of the Binding Pocket.Journal of medicinal chemistry · 2022Article
- Enantiomer-specific activities of an LRH-1 and SF-1 dual agonist.Scientific reports · 2020Article
- Development of a new class of liver receptor homolog-1 (LRH-1) agonists by photoredox conjugate addition.Bioorganic & medicinal chemistry letters · 2020Article
- Development of a Versatile and Sensitive Direct Ligand Binding Assay for Human NR5A Nuclear Receptors.ACS medicinal chemistry letters · 2020Article
- Methyl-Sensing Nuclear Receptor Liver Receptor Homolog-1 Regulates Mitochondrial Function in Mouse Hepatocytes.Hepatology (Baltimore, Md.) · 2020Article
- Development of the First Low Nanomolar Liver Receptor Homolog-1 Agonist through Structure-guided Design.Journal of medicinal chemistry · 2019Article
- The nuclear receptor superfamily: A structural perspective.Protein science : a publication of the Protein Society · 2018Review
- Insights into the mechanism of the PIK3CA E545K activating mutation using MD simulations.Scientific reports · 2018Article
- Development of Hybrid Phospholipid Mimics as Effective Agonists for Liver Receptor Homologue-1.ACS medicinal chemistry letters · 2018Article
- Solution Nuclear Magnetic Resonance Studies of the Ligand-Binding Domain of an Orphan Nuclear Receptor Reveal a Dynamic Helix in the Ligand-Binding Pocket.Biochemistry · 2018Article
- Structure and Dynamics of the Liver Receptor Homolog 1-PGC1Molecular pharmacology · 2017Article
- Crystal Structures of the Nuclear Receptor, Liver Receptor Homolog 1, Bound to Synthetic Agonists.The Journal of biological chemistry · 2016Article
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
Phospholipids (PLs) are unusual signaling hormones sensed by the nuclear receptor liver receptor homolog-1 (LRH-1), which has evolved a novel allosteric pathway to support appropriate interaction with co-regulators depending on ligand status. LRH-1 plays an important role in controlling lipid and cholesterol homeostasis and is a potential target for the treatment of metabolic and neoplastic diseases. Although the prospect of modulating LRH-1 via small molecules is exciting, the molecular mechanism linking PL structure to transcriptional co-regulator preference is unknown. Previous studies showed that binding to an activating PL ligand, such as dilauroylphosphatidylcholine, favors LRH-1's interaction with transcriptional co-activators to up-regulate gene expression. Both crystallographic and solution-based structural studies showed that dilauroylphosphatidylcholine binding drives unanticipated structural fluctuations outside of the canonical activation surface in an alternate activation function (AF) region, encompassing the β-sheet-H6 region of the protein. However, the mechanism by which dynamics in the alternate AF influences co-regulator selectivity remains elusive. Here, we pair x-ray crystallography with molecular modeling to identify an unexpected allosteric network that traverses the protein ligand binding pocket and links these two elements to dictate selectivity. We show that communication between the alternate AF region and classical AF2 is correlated with the strength of the co-regulator interaction. This work offers the first glimpse into the conformational dynamics that drive this unusual PL-mediated nuclear hormone receptor activation.
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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.