The dynamics of agonist-β₂-adrenergic receptor activation induced by binding of GDP-bound Gs protein
Abstract
There is considerable uncertainty about the mechanism by which the β₂-adrenergic receptor (β₂AR) is activated. Here we use molecular metadynamics computations to predict the mechanism by which an agonist induces the activation of the β₂AR and its cognate Gs protein. We found that binding agonist alone to the inactive β₂AR does not break the ionic lock and hence does not drive the β₂AR towards the activated conformation. However, we found that attaching the inactive Gs protein to the agonist-bound inactive β₂AR (containing the ionic lock) leads to partial insertion of Gαs-α5 into the core of β₂AR, which breaks the ionic lock, leading to activation of the Gs protein coupled to β₂AR. Upon activation, the Gαs protein undergoes a remarkable opening of the GDP binding pocket, making the GDP available for exchange or release. Concomitantly, Gαs-α5 undergoes a remarkable expansion in the β₂AR cytoplasmic region after the ionic lock is broken, inducing TM6 to displace outward by ~5 Å from TM3.
Additional Information
© The Author(s), under exclusive licence to Springer Nature Limited 2023. A.M., S.-K.K. and W.A.G. acknowledge support from the NIH (R01HL155532 and R35HL150807). Contributions. W.A.G. and A.M. designed the project. A.M. carried out all calculations. A.M. and S.-K.K. prepared all figures and tables and the Supplementary Information. A.M. wrote the manuscript with W.A.G. and S.-K.K. Data availability. All data generated or analysed during this study are included in this published Article (and its Supplementary Information files). We deposited (https://figshare.com/articles/dataset/free_energy_files/22217674) the metadynamics protocol and associate free-energy results along with the initial and final protein complex structures. Source data are provided with this paper. Code availability. GROMACS (https://www.gromacs.org/) and Plumed (https://www.plumed.org/) are all available as open source. The authors declare no competing interests.Attached Files
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Additional details
- Eprint ID
- 122074
- DOI
- 10.1038/s41557-023-01238-6
- Resolver ID
- CaltechAUTHORS:20230630-524959000.9
- R01HL155532
- NIH
- R35HL150807
- NIH
- Created
-
2023-07-01Created from EPrint's datestamp field
- Updated
-
2023-07-13Created from EPrint's last_modified field