Abstract
Through their coupling to G proteins, G Protein-Coupled Receptors (GPCRs) trigger cellular responses to various signals. Some recent experiments have interestingly demonstrated that the G protein can also act on the receptor by favoring a closed conformation of its orthosteric site, even in the absence of a bound agonist. In this work, we explored such an allosteric modulation by performing extensive molecular dynamics simulations on the adenosine A2 receptor (A2aR) coupled to the Mini-Gs protein. In the presence of the Mini-Gs, we confirmed a restriction of the receptor’s agonist binding site that can be explained by a modulation of the intrinsic network of contacts of the receptor. Of interest, we observed similar effects with the C-terminal helix of the Mini-Gs, showing that the observed effect on the binding pocket results from direct local contacts with the bound protein partner that cause a rewiring of the whole receptor’s interaction network.
Highlights
G protein-coupled receptors (GPCRs) constitute the largest family of human membrane receptors and are involved in numerous physiological processes
We proposed to explore the hypothesis of the stabilization of a closed conformation of the receptor by a G protein and to supply a dynamical view of this process
We focused on the effect of the G protein upon the unbound receptor and performed molecular dynamics (MD) simulations to study the allosteric signaling from the intracellular partner to the agonist site
Summary
G protein-coupled receptors (GPCRs) constitute the largest family of human membrane receptors and are involved in numerous physiological processes. The simulations have benefited enormously from the structural data accumulated in recent years, that culminated in the structural resolution of complexes formed by the GPCR bound to different heterotrimeric G proteins[14,15,16,17] These structures revealed details of the interaction between receptor and G protein and established a basis for the comprehension of signal transmission from the agonist-bound receptor to the G protein. It has been shown that the G protein slows the dissociation of ligands once they are bound to the site, resulting in the enhanced agonist affinity observed for many GPCRs in the presence of G protein[20] These observations led to the hypothesis that the G protein stabilizes a closed conformation of the receptor, with a restricted access to the agonist binding site[20]. Our model system was the adenosine A2 receptor (A2aR), a prototypical class A GPCR, coupled to Mini-Gs (Fig. 1), an engineered protein that binds to A2aR through an interface similar to the one between Gs and β2AR21,22
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