Structural and Dynamics Insights into Melatonin Binding to MT1 Receptor.

Melatonin (MLT) (N-acetyl-5-methoxytryptamine), mainly acting through its two receptors MT1 and MT2, plays a crucial role in regulating circadian rhythms. In addition, MLT has antidepressant, anti-inflammatory, anti-tumor, antioxidant, locomotor activity-regulating, vascular, and neuroprotective effects. Despite recent reports on X-ray free-electron laser and cryo-EM structures of MT1 receptor in complex with agonists, such as agomelatine, 2-phenylmelatonin and ramelteon, a detailed high-resolution description of the MT1 binding by melatonin under near to native (physiological) conditions is still missing. To this aim, we used isolated cellular membranes overexpressing MT1 receptors to conduct a high-resolution nuclear magnetic resonance interaction study. Combined with computational methodologies such as homology modeling, molecular docking and molecular dynamics simulations, this approach provides significant structural and dynamical insights into the interaction between MT1 receptor and melatonin. We found that MLT interacts, through hydrophobic interactions, with the orthosteric binding pocket enhancing receptor motions that in turn facilitate local rearrangements in the cytoplasmic portion of MT1.