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A staggering 50–70 million US adults suffer with a sleeping disorder. Many turn to insomnia medications, such as melatonin receptor agonists, in the quest for a good night’s sleep. However, there is still ambiguity as to the exact role melatonin plays in regulating the circadian rhythm and sleep patterns – making the development of safe, efficacious drugs to combat sleep disorders a challenge.



A team of researchers has now created 3D maps of MT 1 and MT 2 melatonin receptors revealing the structural basis of the selectivity of each receptor subtype. Whilst MT 1 and MT 2 have some conserved ligand-binding site residues, there are “notable conformational variations” and differences in [3H] melatonin dissociation kinetics. The team’s paper was published in Nature, April 24, 2019.



The receptor structures were revealed using a laser that captures “stop-action” pictures of the receptor’s atoms and molecules in motion, via X-rays.



Vadim Cherezov, corresponding author of the study, commented on the study in a recent press release: "Our goal is to provide the structural information to other researchers who can use it for designing new drug compounds or to study mutations of these receptors in patients."



This information has the potential to inspire the development of novel drugs capable of tackling sleep disorders, as well as other conditions linked to melatonin including cancer and Type 2 diabetes.



The researchers intend to use this structural information to design molecules that target and bind to each of the two melatonin receptors – which they can then monitor to determine their potential effects.



Melatonin is a hormone produced in the body’s pineal gland – located near the center of the brain. Humans respond to changes in daylight via the pineal gland. During the day the pineal gland is “inactive”, however as daylight fades and darkness descends, the gland becomes “active” and produces more melatonin which is then released. The released melatonin then binds to MT 1 and MT 2 receptors on the surface of your cells, and you begin to feel less alert. Before dawn, the level of melatonin decreases, signaling that it is time to wake up.



Wei Liu, another of the paper’s authors, highlights the importance of identifying differences in the receptors: "By comparing the 3D structures of the MT 1 and MT 2 receptors, we can better discern the unique, structural differences that distinguish the two receptors from each other -- and their roles in the biological clock."



"Armed with this knowledge, it becomes easier to design drug-like molecules that will bind to only one receptor or the other, but not both. This selective binding is important as it will minimize unwanted side-effects."



Reference: Johansson, LC, et al. XFEL structures of the human MT 2 melatonin receptor reveal the basis of subtype selectivity. Nature (2019) DOI: https://doi.org/10.1038/s41586-019-1144-0



