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

Minfei Su, Lan Zhu, Yixiao Zhang, Navid Paknejad, Raja Dey, Jianyun Huang, Ming Yue Lee, Dewight Williams, Kelsey D. Jordan, Edward T. Eng, Oliver P. Ernst, Joel R. Meyerson, Richard K. Hite, Thomas Walz, Wei Liu, Xin Yun Huang

Research output: Contribution to journalArticlepeer-review

45 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)59-71.e4
JournalMolecular Cell
Issue number1
StatePublished - Oct 1 2020


  • G-protein
  • G-protein-coupled receptor
  • activation of G-proteins
  • cardiac disease
  • cryo-electron microscopy
  • signal transduction
  • structural biology
  • β1-adrenergic receptor

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology


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