Venue : Salle Pyramide (Centre Broca Nouvelle-Aquitaine)
Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 279 Campus
Drive, Stanford, CA 94305, USA
Invited by Daniel Choquet
Investigation of G–protein specificity and biased agonism at the beta–2 adrenergic receptor (β 2AR)
The beta–2–adrenergic receptor (β2AR) is a prototypical G–protein coupled receptor (GPCR). In cardiomyocytes, β2AR couples to the G–protein subtypes Gs and Gi to regulate cardiac function. We used this system to investigate the molecular determinants of biased agonism and G–protein specificity. We developed a Gi–biased agonist, LM189, that we used to obtain
the cryo–EM structure of the β2AR–Gi complex. Spectroscopic investigations show that distinct intermediate states, differentially stabilized by balanced and biased ligands, contribute to G–protein specificity. Understanding the basis of specificity and bias is important to design safer drugs that target GPCRs with reduced side effects.