Melatonin (N-acetyl-5-methoxytryptamine) activates melatonin receptors (MT₁ and MT₂), which are one of the G_i-coupled class A GPCRs and transduce inhibitory signaling by inhibiting the adenylyl cyclase (AC). Melatonin thus induces our sleep and modulates our circadian rhythm, and melatonin receptors have long been regarded as an important therapeutic target for an insomnia. Although melatonin itself serves as a sleep-inducing supplement, its property is not enough to use clinically, because it is rapidly cleared from our body. Therefore, a lot of melatonin analogs with prolonged release properties have been developed so far, such as ramelteon, agomelatine, tasimelteon. 
Recently reported crystal structures of ligand-bound MT₁ and MT₂ elucidated the structural basis of ligand entry and recognition, but the molecular mechanism of the ligand-induced MT₁ structural change that would lead to G_i-coupling remains unclear.
Here we report the cryo-EM structure of the MT₁-G_i signaling complex at 3.3 Å resolution. The structure reveals the receptor activation mechanism, in which the ligand-induced conformational changes are propagated to the G-protein coupling interface. As compared to other G_i-coupled receptors, MT1 exhibits a large outward movement of TM6, which is considered to be a specific feature of G_s-coupled receptors. The structural comparison among the G_i- and G_s-complexes demonstrated the conformational diversity of the C-terminal entry of the G_i protein, suggesting the loose and variable interactions at the helix end. These notions, together with our biochemical and computational analyses, highlight the different binding modes of Gαi and provide the basis for the selectivity of G-protein signaling.