 The G-protein-first mechanism is a process whereby G-protein-coupled receptors, GPCRs, activated by first binding to the inactive G-protein, which then opens up the intracellular region of the receptor to allow for further signalling. This process is observed in the three closest subtypes of opioid receptors, or, or, or. For these receptors, the agonist binds to the extracellular domain of the receptor, but it is only when bound to the inactive G-protein that the intracellular region of the receptor is opened up. This allows for the G-protein to be recruited to the receptor, thus initiating the signal transduction cascade. This article was authored by Amir Hosein-Mafi, Sakyan Kim, and William A. Goddard.