biostudies-literatureMusille PMAmerican Heart AssociationNational Institute of Environmental Health SciencesDepartment of Energy, Labor and Economic GrowthNIDDK NIH HHSNational Institute of Diabetes and Digestive and Kidney DiseasesNIEHS NIH HHSNational Institute of General Medical SciencesNIGMS NIH HHSNational Science Foundation1411-26https://www.ebi.ac.uk/biostudies/studies/S-EPMC4714224biostudies-literatureUnknown291(3)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 anThe Journal of biological chemistryUnexpected Allosteric Network Contributes to LRH-1 Co-regulator Selectivity.PMC4714224R01GM110387T32ES012870T32 ES01287012PRE12060583R01 DK095750R01DK095750R01 GM110387DE-AC02–05CH11231MCB-1149521Kossmann BROrtlund EAKohn JAIvanov IMusille PMfalseUnexpected Allosteric Network Contributes to LRH-1 Co-regulator Selectivity.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 an2016-01-01T00:00:00Z2016 Jan2025-04-19T08:34:09.485Z2019-03-27T02:06:56ZS-EPMC47142242655387610.1074/jbc.M115.66287410.1074/jbc.m115.662874