Cryo-EM structure of the human MT 1 –G i signaling complex

Melatonin receptors (MT 1 and MT 2 ) transduce inhibitory signaling by melatonin ( N -acetyl-5-methoxytryptamine), which is associated with sleep induction and circadian rhythm modulation. Although recently reported crystal structures of ligand-bound MT 1 and MT 2 elucidated the basis of ligand entry and recognition, the ligand-induced MT 1 rearrangement leading to G i -coupling remains unclear. Here we report a cryo-EM structure of the human MT 1 –G i signaling complex at 3.3 Å resolution, revealing melatonin-induced conformational changes propagated to the G-protein-coupling interface during activation. In contrast to other G i -coupled receptors, MT 1 exhibits a large outward movement of TM6, which is considered a specific feature of G s -coupled receptors. Structural comparison of G i and G s complexes demonstrated conformational diversity of the C-terminal entry of the G i protein, suggesting loose and variable interactions at the end of the α5 helix of G i protein. These notions, together with our biochemical and computational analyses, highlight variable binding modes of Gα i and provide the basis for the selectivity of G-protein signaling.