EMD-22357
Structural Basis of the Activation of Heterotrimeric Gs-protein by Isoproterenol-bound Beta1-Adrenergic Receptor
EMD-22357
Single-particle2.6 Å
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Map released: 02/09/2020
Last modified: 20/11/2024
Sample Organism:
Bos taurus,
Lama glama,
Meleagris gallopavo
Sample: Isoproterenol bound beta1 adrenergic receptor in complex with heterotrimeric Gs protein
Fitted models: 7jjo (Avg. Q-score: 0.599)
Deposition Authors: Su M, Zhu L
Sample: Isoproterenol bound beta1 adrenergic receptor in complex with heterotrimeric Gs protein
Fitted models: 7jjo (Avg. Q-score: 0.599)
Deposition Authors: Su M, Zhu L
Structural Basis of the Activation of Heterotrimeric Gs-Protein by Isoproterenol-Bound beta 1 -Adrenergic Receptor.
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
(2020) Mol Cell , 80 , 59
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(2020) Mol Cell , 80 , 59
Abstract:
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.
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.