The dynamics of agonist-β-adrenergic receptor activation induced by binding of GDP-bound Gs protein.

There is considerable uncertainty about the mechanism by which the β-adrenergic receptor (βAR) is activated. Here we use molecular metadynamics computations to predict the mechanism by which an agonist induces the activation of the βAR and its cognate Gs protein. We found that binding agonist alone to the inactive βAR does not break the ionic lock and hence does not drive the βAR towards the activated conformation. However, we found that attaching the inactive Gs protein to the agonist-bound inactive βAR (containing the ionic lock) leads to partial insertion of Gαs-α5 into the core of βAR, which breaks the ionic lock, leading to activation of the Gs protein coupled to βAR. 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 βAR cytoplasmic region after the ionic lock is broken, inducing TM6 to displace outward by ~5 Å from TM3.