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Structural Insight into G Protein-Coupled Receptor Signaling Efficacy and Bias between Gs and ?-Arrestin.

ABSTRACT: G protein-coupled receptors (GPCRs) form the largest family of membrane proteins involved in signal transduction. Because of their ability to regulate a wide range of cellular responses and their dysregulation being associated with many diseases, GPCRs remain a key therapeutic target for several clinical indications. In recent years, it has been demonstrated that ligands for a given receptor can engage distinct pathways with different relative efficacies, a concept known as biased signaling or functional selectivity. However, the structural determinants of this phenomenon remain poorly understood. Using the ?2-adrenergic receptor as a model, we identified a linker residue (L1243.43) between the known PIF and NPxxY structural motifs, that plays a central role in the differential efficacy of biased ligands toward the Gs and ?-arrestin pathways. Given the high level of conservation of this linker residue, the study provides structural explanations for biased signaling that can be extrapolated to other GPCRs.

SUBMITTER: Picard LP 

PROVIDER: S-EPMC7088954 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Structural Insight into G Protein-Coupled Receptor Signaling Efficacy and Bias between Gs and β-Arrestin.

Picard Louis-Philippe LP   Schonegge Anne-Marie AM   Bouvier Michel M  

ACS pharmacology & translational science 20190403 3

G protein-coupled receptors (GPCRs) form the largest family of membrane proteins involved in signal transduction. Because of their ability to regulate a wide range of cellular responses and their dysregulation being associated with many diseases, GPCRs remain a key therapeutic target for several clinical indications. In recent years, it has been demonstrated that ligands for a given receptor can engage distinct pathways with different relative efficacies, a concept known as biased signaling or f  ...[more]

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