biostudies-literatureMoore MNNIDA NIH HHS229-238https://www.ebi.ac.uk/biostudies/studies/S-EPMC12675282biostudies-literatureUnknown648(8092)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 selectively¹ and promise to be safer, more effective medications than compounds that uniformly activate all pathways². 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 mechaniNatureDesigning allosteric modulators to change GPCR G protein subtype selectivity.PMC12675282R01 DA061773UH3 DA050316R00 DA048970P30 DA048742F31 DA062411Person KLRobleto VLOlson SHMoore MNSlosky LMFoster NBarak LSKrusemark CLJackson MRInoue AMarron Fernandez de Velasco EAlwin ARSheedlo MJRay CfalseDesigning allosteric modulators to change GPCR G protein subtype selectivity.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 selectively¹ and promise to be safer, more effective medications than compounds that uniformly activate all pathways². 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 mechani2025-01-01T00:00:00Z2025 Dec2026-07-15T13:51:41.323Z2026-07-05T03:11:28.93ZS-EPMC126752824112589410.1038/s41586-025-09643-2