MT1

MT1 is a high-affinity melatonin G protein-coupled receptor (GPCR) that mediates melatonin actions in sleep and circadian biology^[1]. Mechanistically, human MT1 forms an activated MT1-G_i signaling complex after melatonin binding, linking ligand recognition to G-protein coupling^[2]. Functional studies associate MT1 with neuronal firing, arterial vasoconstriction, cancer-cell proliferation, reproductive regulation, and metabolic functions^[3]. In retinal models, MT1/MT2 heteromers mediate melatonin control of rod photoreceptor light sensitivity, showing that MT1 can act within receptor complexes rather than only as an isolated receptor^[4]. In disease-relevant models, MT1 knockout mice show melancholic-like behaviors and circadian neurobiological abnormalities, supporting MT1-focused experimental designs in neuropsychopharmacology^[5]. Compared with MT2, MT1 has a distinct structural basis for ligand recognition, while MT2 structures reveal separate determinants of subtype selectivity^[6][7]. For experimental applications, cryo-EM and XFEL structures with agonists such as melatonin, ramelteon, and 2-iodomelatonin support structure-guided design of melatonergic ligands, although subtype-selective drug design remains challenging because MT1 and MT2 share highly similar orthosteric binding pockets^[6][8].