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 beta(2)-adrenergic receptor (beta(2)AR) is activated. Here we use molecular metadynamics computations to predict the mechanism by which an agonist induces the activation of the beta(2)AR and its cognate Gs protein. We found that binding agonist alone to the inactive beta(2)AR does not break the ionic lock and hence does not drive the beta(2)AR towards the activated conformation. However, we found that attaching the inactive Gs protein to the agonist-bound inactive beta(2)AR (containing the ionic lock) leads to partial insertion of G alpha s-alpha 5 into the core of beta(2)AR, which breaks the ionic lock, leading to activation of the Gs protein coupled to beta(2)AR. Upon activation, the G alpha s protein undergoes a remarkable opening of the GDP binding pocket, making the GDP available for exchange or release. Concomitantly, G alpha s-alpha 5 undergoes a remarkable expansion in the beta(2)AR cytoplasmic region after the ionic lock is broken, inducing TM6 to displace outward by similar to 5 A from TM3.