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

Molecular cell, 2020-10, Vol.80 (1), p.59-71.e4 [Peer Reviewed Journal]

2020 Elsevier Inc. ;ISSN: 1097-2765 ;EISSN: 1097-4164 ;DOI: 10.1016/j.molcel.2020.08.001 ;PMID: 32818430

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  • Title:
    Structural Basis of the Activation of Heterotrimeric Gs-Protein by Isoproterenol-Bound β1-Adrenergic Receptor
  • Author: Su, Minfei ; Zhu, Lan ; Zhang, Yixiao ; Paknejad, Navid ; Dey, Raja ; Huang, Jianyun ; Lee, Ming-Yue ; Williams, Dewight ; Jordan, Kelsey D. ; Eng, Edward T. ; Ernst, Oliver P. ; Meyerson, Joel R. ; Hite, Richard K. ; Walz, Thomas ; Liu, Wei ; Huang, Xin-Yun
  • Subjects: activation of G-proteins ; cardiac disease ; cryo-electron microscopy ; G-protein ; G-protein-coupled receptor ; signal transduction ; structural biology ; β1-adrenergic receptor
  • Is Part Of: Molecular cell, 2020-10, Vol.80 (1), p.59-71.e4
  • Description: 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. [Display omitted] •Cryo-EM structure of β1-adrenergic receptor and Gs at 2.6-Å resolution•Network of interactions within Gαs are disrupted by β1-AR•Rotational opening of the α-helical domain of Gαs during its activation•Functional studies of critical residues on β1-AR involved in the activation of Gs Su et al. report the cryo-EM structure of the complex of isoproterenol-bound β1-adrenergic receptor and heterotrimeric Gs-protein. The structural and functional studies reveal insights into the activation of Gs by β1-adrenergic receptor. This work advances our understanding of the control of heart rate and contractility by the nervous system and hormones.
  • Publisher: Elsevier Inc
  • Language: English
  • Identifier: ISSN: 1097-2765
    EISSN: 1097-4164
    DOI: 10.1016/j.molcel.2020.08.001
    PMID: 32818430
  • Source: Cell Press Free Archives
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