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Download fileStructural Insight into G Protein-Coupled Receptor Signaling Efficacy and Bias between Gs and β‑Arrestin
journal contribution
posted on 2019-04-03, 00:00 authored by Louis-Philippe Picard, Anne-Marie Schonegge, Michel BouvierG 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.