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Roles of Melatonin in Maintaining Mitochondrial Welfare
Published in Shamim I. Ahmad, Handbook of Mitochondrial Dysfunction, 2019
Feres José Mocayar Marón, Emiliano Diez, Russel J. Reiter, Walter Manucha
Due to its amphipathic nature, melatonin crosses membranes readily, which then exerts effects independent of its membrane receptors in all cells49. However, the presence of several targets could explain melatonin´s pleiotropism. Among others targets are: melatonin G-protein-coupled receptors in the plasma membrane (e.g., MT1 and MT2)50; binding to intracellular proteins, such as calmodulin, sirtuins, quinone reductase, tubulin, and calreticulin; and orphan nuclear receptors (e.g., RZR/RORα: retinoid-related orphan nuclear hormone receptor and GPR50: X-linked melatonin-related orphan receptor)51. Melatonin´s antioxidant proprieties are the result of direct free radical scavenging and indirect pathways which involves membrane or mitochondrial receptors52,53. It was recently reported that the transmission of microRNAs by exosomes might contribute to melatonin´s actions54.
In silico drug discovery of melatonin receptor ligands with therapeutic potential
Published in Expert Opinion on Drug Discovery, 2022
Gian Marco Elisi, Laura Scalvini, Alessio Lodola, Annalida Bedini, Gilberto Spadoni, Silvia Rivara
Overall, the lack of a clear ligand recognition pattern, due, for example, to the absence of ionic interactions between charged ligand groups and protein residues as in aminergic neurotransmitter receptors, the availability of nonconclusive mutagenesis data and the limited homology of melatonin receptors with template receptors misled the generation of models that were not able to correctly reproduce key polar interactions with N4.60 and the glutamine from extracellular loop (ECL) 2. On the other hand, the role of ECL2 in shaping the ligand binding site was properly recognized in rhodopsin-based models [23] that were characterized by a deeply buried cavity with sealed extracellular entrance, as happens in rhodopsin crystals. In a more recent work, the role of ECL2 in ligand recognition and receptor structure was investigated. Data from mutagenesis experiments and chimeric receptors, derived from MT1 and the highly homologous but functionally inactive GPR50, were rationalized using homology models. ECL2 was modeled as a β-hairpin structure covering the binding site, based on the geometry of ECL2 of rhodopsin, which was the closest template [73].