Structural basis of the activation of heterotrimeric Gs-protein by isoproterenol-bound β1-adrenergic receptor Journal Article
| Authors: | 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. |
| Article Title: | 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. © 2020 Elsevier Inc. Su et al. report the cryo-EM structure of the complex of isoproterenol-bound β1-adrenergic receptor and heterotrimeric Gs-protein. The structural and functional studies reveal insights into the activation of Gs by β1-adrenergic receptor. This work advances our understanding of the control of heart rate and contractility by the nervous system and hormones. © 2020 Elsevier Inc. |
| Keywords: | signal transduction; controlled study; protein domain; animal; metabolism; animals; carboxy terminal sequence; cell line; protein binding; enzyme activation; chemistry; regulatory mechanism; molecular recognition; binding site; crystal structure; hydrogen bond; models, molecular; binding sites; cattle; conformational transition; molecular biology; protein secondary structure; protein structure; guanosine triphosphate; guanine nucleotide binding protein; g protein coupled receptor; protein structure, secondary; molecular model; heart function; protein domains; cryoelectron microscopy; guanosine diphosphate; alpha helix; cryo-electron microscopy; g-protein; g-protein-coupled receptor; structural biology; carbonyl derivative; bovine; article; beta 1 adrenergic receptor; receptors, adrenergic, beta-1; cardiac disease; isoprenaline; activation of g-proteins; β1-adrenergic receptor; stimulatory guanine nucleotide binding protein; tilting; gtp-binding protein alpha subunits, gs; isoproterenol |
| Journal Title: | Molecular Cell |
| Volume: | 80 |
| Issue: | 1 |
| ISSN: | 1097-2765 |
| Publisher: | Cell Press |
| Date Published: | 2020-10-01 |
| Start Page: | 59 |
| End Page: | 71.e4 |
| Language: | English |
| DOI: | 10.1016/j.molcel.2020.08.001 |
| PUBMED: | 32818430 |
| PROVIDER: | scopus |
| PMCID: | PMC7541785 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 2 November 2020 -- Source: Scopus |
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