Designing allosteric modulators to change GPCR G protein subtype selectivity.

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 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 mechani

SUBMITTER: Moore MN 

PROVIDER: S-EPMC12675282 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature