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

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.

journal_name

Mol Cell

journal_title

Molecular cell

authors

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

doi

10.1016/j.molcel.2020.08.001

subject

Has Abstract

pub_date

2020-10-01 00:00:00

pages

59-71.e4

issue

1

eissn

1097-2765

issn

1097-4164

pii

S1097-2765(20)30544-X

journal_volume

80

pub_type

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