Elucidation of a dynamic interplay between guanine nucleotide and the ternary complex of a beta-adrenergic receptor, its agonist and stimulatory G protein
Biophysical Journal(2023)
Abstract
Heterotrimeric G proteins, composed of α, β, and γ subunits, are molecular switches which can be regulated to either turn on or turn off based on their binding to transmembrane G-protein-coupled receptors (GPCRs) and guanine nucleotides, GTP or GDP. Coupled with their receptors, G proteins play a critical role in determining the specificity and temporal characteristics of the cellular responses of a diverse array of extracellular stimuli. G proteins decouple from GPCRs upon GTP binding to their Gα subunits, allowing both Gα and Gβγ to interact with downstream effector proteins. What is the role of GDP and GTP binding in the activation and dissociation of G proteins and what Gα conformational changes does GTP/GDP binding trigger? Answering these questions requires detailed time-resolved structural information. In this study we focused on interactions of GTP and GDP with stimulatory G protein (Gs), which is coupled with a prototypical GPCR, the beta-adrenergic receptor (βAR) using Rosetta modeling and all-atom molecular dynamics simulations. We found that GTP/GDP binding indirectly alters Gsα conformation by causing inter-domain rearrangement while directly causing α5 helix tilting, thus favoring Gsα dissociation. GTP/GDP binding also enhances correlations between Gsα inter-domain arrangement and Gsα conformational changes. Specifically, we found negative correlation between α5 titling angle and α1–α5 stacking which was different from the apo Gs protein case we observed previously. In summary, we analyzed conformational specificities of Gs protein–guanine nucleotide interactions and found correlations between Gs dissociation and its internal domain rearrangement. This provides intrinsic molecular insights into the understanding of G protein activation and may be beneficial for the design of safe and efficacious pharmaceuticals in precisely controlling the signaling properties of βARs.
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Key words
guanine nucleotide,receptor,agonist,beta-adrenergic
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