Structural Basis of the Activation of Heterotrimeric Gs-Protein by Isoproterenol-Bound β1-Adrenergic Receptor
| Autor: | Dewight Williams, Kelsey D. Jordan, Navid Paknejad, Ming-Yue Lee, Joel R. Meyerson, Thomas Walz, Xin-Yun Huang, Yixiao Zhang, Lan Zhu, Edward T. Eng, Minfei Su, Wei Liu, Richard K Hite, Jianyun Huang, Oliver P. Ernst, Raja Dey |
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| Rok vydání: | 2020 |
| Předmět: |
0303 health sciences
Gs alpha subunit G protein Regulator Cell Biology Biology Cell biology 03 medical and health sciences 0302 clinical medicine Structural biology Heterotrimeric G protein Signal transduction Receptor Molecular Biology 030217 neurology & neurosurgery 030304 developmental biology G protein-coupled receptor |
| Zdroj: | Molecular Cell. 80:59-71.e4 |
| ISSN: | 1097-2765 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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