Melatonin receptor structures shed new light on melatonin research

Abstract

The tryptophan derivative melatonin is an evolutionary old molecule that is involved in a pleiotropy of physiological functions. In humans, age-related decline of circulating melatonin levels and/or dysregulation of its circadian synthesis pattern have been associated with several disorders and disease states. Several molecular targets have been proposed for melatonin since its discovery, in 1959. Among them, melatonin MT 1 and MT 2 receptors are the best characterized melatonin targets, mediating melatonin effects in a variety of tissues. They belong to the superfamily of G protein-coupled receptors. Two back-to-back articles published in the "Nature" Journal earlier this year present the first crystal structures of the human MT 1 and MT 2 in its inactive states. Here, we will briefly outline the discovery path of melatonin receptors until their structural elucidation and discuss how these new findings will guide future research toward a better understanding of their function and rational drug design. K E Y W O R D Scrystal structure, dimers, GPCR, melatonin

Melatonin: Effects on Cartilage Homeostasis and Therapeutic Prospects in Cartilage-related Diseases

“…The chemical name and molecular formula of melatonin are N-acetyl-5methoxytryptamine and C13H16N2O2, respectively. Its properties include a relative molecular mass of 232.27 grams per mole and a melting point of 116-118℃, and pure melatonin consists of pale yellow leaf-like crystals [19].…”

Melatonin receptor ligands: A pharmaco‐chemical perspective

“…The difficulties in finding MT 1 ‐selective agonists can be explained, in part, by differences in the geometry of the orthosteric binding pockets in MT 1 and MT 2 crystal structures recently discussed in two commentary articles 137,138 . Despite high degree of conservation between the agonist binding pockets of MT 1 and MT 2 , the structural differences reveal why MT 2 ‐selective ligands were much more easily discovered.…”

Melatonin Target Proteins: Too Many or Not Enough?

“…The binding pose of the melatonin derivative 2-phenylmelatonin (2-PMT) proved to be very similar for both receptors with identical key residues, including the participation of the extracellular loop 2 (ECL2) (N 4.60 , F ECL2 , Q ECL2 , and N 6.52 ) (superscripts represent Ballesteros–Weinstein nomenclature; Figures 1A,B). Interestingly, the binding pocket in the MT 1 structure has one lateral ligand entry channel (from the membrane environment), whereas two ligand entry channels, the lateral one, and an additional one from the extracellular side, are visible in the MT 2 structure (52–54). These different ligand entry channels as well as their different widths and differences in the overall volume of the pockets with the pocket of MT 2 being about 50 Å 3 larger than that of MT 1 , offer future opportunities for subtype selective drug development.…”