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Understanding the mechanisms of activation of G-protein– coupled receptors (GPCRs) is a major issue in biophysics and pharmacology.
G-protein–coupled receptors (GPCRs) are the largest mammalian transmembrane receptor superfamily. Their variety and role in physiological pathways make them critical drug targets for numerous pathological conditions. Despite the advances in structural biology of GPCRs, we are far away from fully understanding the role of ligand-induced conformational changes (allostery) in this family of receptors. Large structural biology studies have revealed a
two-states (active-inactive) formalism that is unlikely to cover the conformational diversity of this family of receptors. Combining all-atom simulations and free- energy landscape calculations we studied the activation mechanism of the glucagon receptor, a prototypical class B GPCR. In contrast to previous conformational selection hypotheses, we find that both interactions with the peptide and the G protein are necessary to induce the transition to the active state. Mattedi et al. PNAS(2020)
G-protein–coupled receptors (GPCRs) are the largest mammalian transmembrane receptor superfamily. Their variety and role in physiological pathways make them critical drug targets for numerous pathological conditions. Despite the advances in structural biology of GPCRs, we are far away from fully understanding the role of ligand-induced conformational changes (allostery) in this family of receptors. Large structural biology studies have revealed a
two-states (active-inactive) formalism that is unlikely to cover the conformational diversity of this family of receptors. Combining all-atom simulations and free- energy landscape calculations we studied the activation mechanism of the glucagon receptor, a prototypical class B GPCR. In contrast to previous conformational selection hypotheses, we find that both interactions with the peptide and the G protein are necessary to induce the transition to the active state. Mattedi et al. PNAS(2020)