Fig. 6: Schematic illustration of the kinetic aspects of ternary complex formation contributing to G protein selectivity.

Agonist binding favourably shifts efficacy-dependent conformational equilibria between multiple states (inactive I₁, I₂; pre-active P; active A) of a GPCR towards the pre-active and active states. The active state (A) conformation shows a characteristic rotation of the cytoplasmic half of TM6, that promotes interaction with suitable binding partners. G protein interaction with the active or the pre-active state of the receptor leads to ternary complex formation following the displacement of TM6 from the receptor core and opening of the cytoplasmic binding cavity. The rate at which the ternary complexes form depends strongly on the family of G protein and the state the receptor is in. Favourable interactions between the Gα domain of the canonical binding partner and the active state of the GPCR result in substantially faster complex formation, outcompeting other non-canonical G proteins and contributing to selectivity. Only subtle variation in receptor conformation can be observed amongst the complexes with G proteins from different families.