Rational design of biased G protein-coupled receptor agonists.

Activation of most G protein-coupled receptors (GPCRs) initiates several branches of signaling. The consequences of some of these can be therapeutically beneficial, whereas others may cause unwanted side effects. Therefore, search for ligands biasing receptor signaling toward desired directions and away from undesired ones is increasingly popular. Currently, the field is focusing on G protein versus arrestin dichotomy. Arrestin binding to most GPCRs critically depends on receptor phosphorylation by GPCR kinases (GRKs). Existing data suggest that to bias signaling for or against arrestin-mediated branches one needs to enhance or reduce, respectively, the propensity of the receptor to recruit GRKs and become phosphorylated. As GRKs are gatekeepers for arrestin-mediated signaling, rational design of biased ligands should be based on the comparison of receptor complexes with G proteins with the structures of GPCRs bound to GRKs rather than arrestins. The same GPCR may engage distinct GRK subtypes differently, establishing an additional layer of bias. SIGNIFICANCE STATEMENT: Because arrestin binding to G protein-coupled receptors (GPCRs) requires prior receptor phosphorylation, GPCR-GPCR kinase complexes, not GPCR complexes with arrestins, should be compared to GPCR-G protein complexes to guide the design of G protein- and arrestin-biased ligands.