{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"omics_type":["Unknown"],"submitter":["Moore MN"],"funding":["NIDA NIH HHS"],"pubmed_abstract":["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 "],"journal":["bioRxiv : the preprint server for biology"],"pagination":["2024.11.20.624209"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC11601581"],"repository":["biostudies-literature"],"pubmed_title":["Design of allosteric modulators that change GPCR G protein subtype selectivity."],"pmcid":["PMC11601581"],"funding_grant_id":["R01 DA061773","UH3 DA050316","R00 DA048970","P30 DA048742"],"pubmed_authors":["Person KL","Olson SH","Alwin A","Moore MN","Slosky LM","Foster N","Barak LS","Jackson MR","Fernandez de Velasco EM","Krusemark C","Inoue A","Sheedlo MJ","Ray C"],"additional_accession":[]},"is_claimable":false,"name":"Design of allosteric modulators that change GPCR G protein subtype selectivity.","description":"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 ","dates":{"release":"2024-01-01T00:00:00Z","publication":"2024 Nov","modification":"2026-04-07T15:09:38.675Z","creation":"2026-04-07T14:24:01.49Z"},"accession":"S-EPMC11601581","cross_references":{"pubmed":["39605353"],"doi":["10.1101/2024.11.20.624209"]}}