Melatonin receptors (MT₁ and MT₂) 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 MT₁ and MT₂ elucidated the basis of ligand entry and recognition, the ligand-induced MT₁ rearrangement leading to G_i-coupling remains unclear. Here we report a cryo-EM structure of the human MT₁–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, MT₁ 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.

褪黑激素受体（MT ₁和 MT ₂）通过褪黑激素（N-乙酰-5-甲氧基色胺）转导抑制性信号，这与睡眠诱导和昼夜节律调节有关。尽管最近报道的配体结合的 MT ₁和 MT _{2 的}晶体结构阐明了配体进入和识别的基础，但配体诱导的 MT ₁重排导致 G _i偶联仍不清楚。在这里，我们报告了人类 MT ₁ –G _i的冷冻电镜结构3.3 Å 分辨率的信号复合物，揭示了褪黑激素诱导的构象变化在激活过程中传播到 G 蛋白偶联界面。与其他 G _i偶联受体相比，MT ₁表现出 TM6 的大量向外运动，这被认为是 G _s偶联受体的一个特定特征。的G的结构比较_我和G_小号络合物展示了G的C端条目的构象多样性_我在G的α5螺旋的末端蛋白质，这表明松散和可变相互作用_我蛋白。这些概念，连同我们的生化和计算分析，突出了 Gα _{i 的}可变结合模式 并为 G 蛋白信号的选择性提供基础。