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

Picard LP, Schonegge AM, Bouvier M

Department of Biochemistry and Molecular Medicine, Institute for Research in Immunology and Cancer, Université de Montréal, Montreal, Quebec H3C 3J7, Canada.

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 β2-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 β-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.

ACS Pharmacol Transl Sci 2020;2(3):148-154.

Pubmed ID: 32259053

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