Fig. 4: Model of MOR-mediated G protein activation, in which ligand efficacy dictates binding pose and stabilization of specific conformational states, regulating GDP release rates.

Our data support a model in which efficacy is primarily driven by the transition from a signalling-silent ‘latent’ state to an ‘engaged’ state. This transition results in a hallmark ‘active-like’ MOR conformation and an extended α5 helix, despite the AHD remaining closed. The engaged state is structurally primed for subsequent AHD opening, which is essential for GDP release. Stabilization of the latent state probably reduces nucleotide exchange rates, approximating basal activity seen in receptor-free GDP–Gα_i1β₁γ₂, whereas progression through downstream states accelerates GDP release, thereby enhancing G protein activation.