{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Moore MN"],"funding":["NIDA NIH HHS"],"pagination":["229-238"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC12675282"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["648(8092)"],"pubmed_abstract":["G-protein-coupled receptors (GPCRs) convert extracellular signals into intracellular responses by signalling through 16 subtypes of Gα proteins and two β-arrestin proteins. Biased compounds-molecules that preferentially activate a subset of these proteins-engage therapy-relevant pathways more selectively<sup>1</sup> and promise to be safer, more effective medications than compounds that uniformly activate all pathways<sup>2</sup>. However, the determinants of bias are poorly understood, and we lack rationally designed molecules that select for specific G proteins. Here, using the prototypical class A GPCR neurotensin receptor 1 (NTSR1), we show that small molecules that bind to the intracellular GPCR-transducer interface change G protein coupling by subtype-specific and predictable mechani"],"journal":["Nature"],"pubmed_title":["Designing allosteric modulators to change GPCR G protein subtype selectivity."],"pmcid":["PMC12675282"],"funding_grant_id":["R01 DA061773","UH3 DA050316","R00 DA048970","P30 DA048742","F31 DA062411"],"pubmed_authors":["Person KL","Robleto VL","Olson SH","Moore MN","Slosky LM","Foster N","Barak LS","Krusemark CL","Jackson MR","Inoue A","Marron Fernandez de Velasco E","Alwin AR","Sheedlo MJ","Ray C"],"additional_accession":[]},"is_claimable":false,"name":"Designing allosteric modulators to change GPCR G protein subtype selectivity.","description":"G-protein-coupled receptors (GPCRs) convert extracellular signals into intracellular responses by signalling through 16 subtypes of Gα proteins and two β-arrestin proteins. Biased compounds-molecules that preferentially activate a subset of these proteins-engage therapy-relevant pathways more selectively<sup>1</sup> and promise to be safer, more effective medications than compounds that uniformly activate all pathways<sup>2</sup>. However, the determinants of bias are poorly understood, and we lack rationally designed molecules that select for specific G proteins. Here, using the prototypical class A GPCR neurotensin receptor 1 (NTSR1), we show that small molecules that bind to the intracellular GPCR-transducer interface change G protein coupling by subtype-specific and predictable mechani","dates":{"release":"2025-01-01T00:00:00Z","publication":"2025 Dec","modification":"2026-07-15T13:51:41.323Z","creation":"2026-07-05T03:11:28.93Z"},"accession":"S-EPMC12675282","cross_references":{"pubmed":["41125894"],"doi":["10.1038/s41586-025-09643-2"]}}