G protein coupling and activation of the metabotropic GABAB heterodimer

Metabotropic gamma-aminobutyric acid receptor (GABA(B)R), a class C G protein-coupled receptor (GPCR) heterodimer, plays a crucial role in the central nervous system. Cryo-electron microscopy studies revealed a drastic conformational change upon activation and a unique G protein (GP) binding mode. However, little is known about the mechanism for GP coupling and activation for class C GPCRs. Here, we use molecular metadynamics computations to predict the mechanism by which the inactive GP induces conformational changes in the GABA(B)R transmembrane domain (TMD) to form an intermediate pre-activated state. We find that the inactive GP first interacts with TM3, which further leads to the TMD rearrangement and deeper insertion of the alpha 5 helix that causes the G alpha subunit to open, releasing GDP, and forming the experimentally observed activated structure. This mechanism provides fresh insights into the mechanistic details of class C GPCRs activation expected to be useful for designing selective agonists and antagonists. Despite its crucial role in the central nervous system, little is known about the activation mechanism of GABA(B) receptor. Here, the authors predict that the inactive G protein induces conformational changes of the receptor to form an intermediate state.