The dynamics of agonist-β2-adrenergic receptor activation induced by binding of GDP-bound Gs protein

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.