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

doi:10.1016/j.molcel.2020.08.001

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 journal › Article › peer-review

47 Scopus citations

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 Gα_s. 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 language	English (US)
Pages (from-to)	59-71.e4
Journal	Molecular Cell
Volume	80
Issue number	1
DOIs	https://doi.org/10.1016/j.molcel.2020.08.001
State	Published - Oct 1 2020
Externally published	Yes

Bibliographical note

Funding Information:
We thank members of our research groups for helpful discussion and comments on the manuscript. This work was supported by NIH grant HL130478 (X.-Y.H.), the Josie Robertson Investigators Program (R.K.H.), the Searle Scholars Program (R.K.H.), the Canada Excellence Research Chairs Program (O.P.E.), and CIHR grant 159464 (O.P.E.). The Simons Electron Microscopy Center and the National Resource for Automated Molecular Microscopy located at the New York Structural Biology Center are supported by grants from the NIH National Institute of General Medical Sciences ( GM103310 ), NYSTAR , and the Simons Foundation ( SF349247 ).

Publisher Copyright:
© 2020 Elsevier Inc.

Keywords

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

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Su, M., Zhu, L., Zhang, Y., Paknejad, N., Dey, R., Huang, J., Lee, M. Y., Williams, D., Jordan, K. D., Eng, E. T., Ernst, O. P., Meyerson, J. R., Hite, R. K., Walz, T., Liu, W., & Huang, X. Y. (2020). Structural Basis of the Activation of Heterotrimeric Gs-Protein by Isoproterenol-Bound β₁-Adrenergic Receptor. Molecular Cell, 80(1), 59-71.e4. https://doi.org/10.1016/j.molcel.2020.08.001

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, 'Structural Basis of the Activation of Heterotrimeric Gs-Protein by Isoproterenol-Bound β₁-Adrenergic Receptor', Molecular Cell, vol. 80, no. 1, pp. 59-71.e4. https://doi.org/10.1016/j.molcel.2020.08.001

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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.",

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

note = "Funding Information: We thank members of our research groups for helpful discussion and comments on the manuscript. This work was supported by NIH grant HL130478 (X.-Y.H.), the Josie Robertson Investigators Program (R.K.H.), the Searle Scholars Program (R.K.H.), the Canada Excellence Research Chairs Program (O.P.E.), and CIHR grant 159464 (O.P.E.). The Simons Electron Microscopy Center and the National Resource for Automated Molecular Microscopy located at the New York Structural Biology Center are supported by grants from the NIH National Institute of General Medical Sciences ( GM103310 ), NYSTAR , and the Simons Foundation ( SF349247 ). Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",

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AU - Williams, Dewight

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AU - Liu, Wei

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