Structural Basis of the Activation of Heterotrimeric Gs-Protein by Isoproterenol-Bound β1-Adrenergic Receptor

Cardiac disease remains the leading cause of morbidity and mortality worldwide. The beta(1)-adrenergic receptor (beta(1)-AR) is a major regulator of cardiac functions and is downregulated in the majority of heart failure cases. A key physiological process is the activation of heterotrimeric G-protein Gs by beta(1)-ARs, leading to increased heart rate and contractility. Here, we use cryo-electron microscopy and functional studies to investigate the molecular mechanism by which beta(1)-AR activates Gs. We find that the tilting of alpha 5-helix breaks a hydrogen bond between the sidechain of His373 in the C-terminal alpha 5-helix and the backbone carbonyl of Arg38 in the N-terminal alpha N-helix of Ga-s. Together with the disruption of another interacting network involving Gln59 in the alpha 1-helix, Ala352 in the beta 6-alpha 5 loop, and Thr355 in the alpha 5-helix, these conformational changes might lead to the deformation of the GDP-binding pocket. Our data provide molecular insights into the activation of G-proteins by G-protein-coupled receptors.