biostudies-literatureUnknownMoore MNNIDA NIH HHSG protein-coupled receptors (GPCRs), the largest family of drug targets, can signal through 16 subtypes of Gα proteins. Biased compounds that selectively activate therapy-relevant pathways promise to be safer, more effective medications. The determinants of bias are poorly understood, however, and rationally-designed, G protein-subtype-selective compounds are lacking. Here, using the prototypical class A GPCR neurotensin receptor 1 (NTSR1), we find that small molecules binding the intracellular GPCR-transducer interface change G protein coupling by subtype-specific and predictable mechanisms, enabling rational drug design. We demonstrate that the compound SBI-553 switches NTSR1 G protein preference by acting both as a molecular bumper and a molecular glue. Structurally, SBI-553 occludes G bioRxiv : the preprint server for biology2024.11.20.624209https://www.ebi.ac.uk/biostudies/studies/S-EPMC11601581biostudies-literatureDesign of allosteric modulators that change GPCR G protein subtype selectivity.PMC11601581R01 DA061773UH3 DA050316R00 DA048970P30 DA048742Person KLOlson SHAlwin AMoore MNSlosky LMFoster NBarak LSJackson MRFernandez de Velasco EMKrusemark CInoue ASheedlo MJRay CfalseDesign of allosteric modulators that change GPCR G protein subtype selectivity.G protein-coupled receptors (GPCRs), the largest family of drug targets, can signal through 16 subtypes of Gα proteins. Biased compounds that selectively activate therapy-relevant pathways promise to be safer, more effective medications. The determinants of bias are poorly understood, however, and rationally-designed, G protein-subtype-selective compounds are lacking. Here, using the prototypical class A GPCR neurotensin receptor 1 (NTSR1), we find that small molecules binding the intracellular GPCR-transducer interface change G protein coupling by subtype-specific and predictable mechanisms, enabling rational drug design. We demonstrate that the compound SBI-553 switches NTSR1 G protein preference by acting both as a molecular bumper and a molecular glue. Structurally, SBI-553 occludes G 2024-01-01T00:00:00Z2024 Nov2026-04-07T15:09:38.675Z2026-04-07T14:24:01.49ZS-EPMC116015813960535310.1101/2024.11.20.624209