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

Mol Cell. 2020 Oct 1;80(1):59-71.e4. doi: 10.1016/j.molcel.2020.08.001. Epub 2020 Aug 19.


Cardiac disease remains the leading cause of morbidity and mortality worldwide. The β1-adrenergic receptor (β1-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 β1-ARs, leading to increased heart rate and contractility. Here, we use cryo-electron microscopy and functional studies to investigate the molecular mechanism by which β1-AR activates Gs. We find that the tilting of α5-helix breaks a hydrogen bond between the sidechain of His373 in the C-terminal α5-helix and the backbone carbonyl of Arg38 in the N-terminal αN-helix of Gαs. Together with the disruption of another interacting network involving Gln59 in the α1-helix, Ala352 in the β6-α5 loop, and Thr355 in the α5-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.

Keywords: G-protein; G-protein-coupled receptor; activation of G-proteins; cardiac disease; cryo-electron microscopy; signal transduction; structural biology; β1-adrenergic receptor.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Binding Sites
  • Cattle
  • Cell Line
  • GTP-Binding Protein alpha Subunits, Gs / chemistry*
  • GTP-Binding Protein alpha Subunits, Gs / metabolism*
  • Guanosine Diphosphate / metabolism
  • Guanosine Triphosphate / metabolism
  • Isoproterenol / metabolism*
  • Models, Molecular
  • Protein Binding
  • Protein Domains
  • Protein Structure, Secondary
  • Receptors, Adrenergic, beta-1 / chemistry*
  • Receptors, Adrenergic, beta-1 / metabolism*


  • Receptors, Adrenergic, beta-1
  • Guanosine Diphosphate
  • Guanosine Triphosphate
  • GTP-Binding Protein alpha Subunits, Gs
  • Isoproterenol