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Structural Basis of the Activation of Heterotrimeric Gs-Protein by Isoproterenol-Bound β1-Adrenergic Receptor. Mol Cell 2020 Oct 01;80(1):59-71.e4



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Pubmed Central ID




Scopus ID

2-s2.0-85090205426 (requires institutional sign-in at Scopus site)   33 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.

Author List

Su M, Zhu L, Zhang Y, Paknejad N, Dey R, Huang J, Lee MY, Williams D, Jordan KD, Eng ET, Ernst OP, Meyerson JR, Hite RK, Walz T, Liu W, Huang XY


Wei Liu PhD Associate Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin
Lan Zhu PhD Assistant Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Binding Sites
Cell Line
GTP-Binding Protein alpha Subunits, Gs
Guanosine Diphosphate
Guanosine Triphosphate
Models, Molecular
Protein Binding
Protein Domains
Protein Structure, Secondary
Receptors, Adrenergic, beta-1