A third of all Americans have difficulty with sleeping, and many of them turn to melatonin supplements to catch some Zs. However, scientists don’t fully understand melatonin’s role in the biological clock, which has made it difficult to develop drugs for sleep disorders without several side effects.
Now, in back-to-back papers in Nature, an international team of scientists has shed much-needed light on melatonin’s effects, opening the door to the development of new drugs for sleep disorders and other serious health conditions. They developed 3D models of the tiny antennae called receptors, which are located on the surface of cells and help synchronize the body’s internal clock with the day and night cycle.
“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,” said co-corresponding author Vadim Cherezov, PhD, a scientist at the Bridge Institute at the University of Southern California Michelson Center for Convergent Bioscience.
His team used free electron crystallography to solve the structure of the melatonin receptors. Then the lab of Bryan L. Roth, MD, PhD, the Michael Hooker Distinguished Professor of Pharmacology at the UNC School of Medicine conducted extensive analyses to generate a comprehensive map of how melatonin and other drugs interact with the MT1 and MT2 melatonin receptors.
“This data will help us design drugs that interact only with these receptors, with the hope we can treat a variety of conditions including diabetes, cancers, and sleep disorders, in a more targeted way,” said Roth, co-corresponding author and member of the UNC Lineberger Comprehensive Cancer Center and the UNC Neuroscience Center.
Melatonin is generated in the center of the brain by the pineal gland, once described by the philosopher Descartes as the “soul” of the brain and body.
Humans respond naturally to daylight changes through the pineal gland, near the hypothalamus. As night falls, the gland produces more melatonin, which then binds to the MT1 and MT2 receptors of the cells. Before dawn, the gland decreases melatonin levels, signaling that it’s time to wake.
MT1 and MT2 are among an estimated 800 receptors in the human body. These receptors, known as G protein-coupled receptors (GPCRs) appear on the surface of a cell. The receptors act as a sort of email inbox, relaying information into the cell to set off a cascade of activity.
About a third of all drugs on the market are designed to bind with GPCRs. Each receptor has a different role in regulating functions in the body, many of which are critical for basic survival, such as hunger and reproductivity. The bulk of these receptors also have some role in the human olfactory system — taste and smell.
Scientists around the world have obtained structures of less than one-tenth of these receptors so far. Bryan Roth’s lab is a leader in this field, most recently having solved the structures of an
opioid receptor, a dopamine receptor, and two serotonin receptors – one of which LSD binds to. All of this work represents a much needed step toward creating better medications without severe side effects.
MT1 and MT2 are the latest receptors Roth and colleagues have mapped.
“By comparing the 3D structures of the MT1 and MT2 receptors, we can better discern the unique, structural differences that distinguish the two receptors from each other — and their roles in the biological clock,” said co-corresponding author Wei Liu, PhD, of Arizona State University’s Biodesign Institute. “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.”
The structures of both receptors were obtained using a laser, called the Linac Coherent Light Source (LCLS) at the SLAC National Accelerator Laboratory, which uses X-rays to take stop-action pictures of the receptor atoms and molecules in motion.
“Due to the tiny size of the crystals, it wouldn’t have been possible to make these measurements anywhere other than LCLS,” says co-author Alex Batyuk, a scientist at SLAC National Accelerator Laboratory. “Because of the extreme brightness and short pulse duration of LCLS, we were able to collect hundreds of thousands of images of the crystals to figure out the three-dimensional structure of these receptors.”
UNC authors are Xi-Ping Huang, Reid H. J. Olsen, Alexandra R. Tribo, and John McCorvy, who is now at the University of Wisconsin. Roth holds a joint appointment at the UNC Eshelman School of Pharmacy.
The research is the result of a collaboration among scientists at USC, Arizona State University’s Biodesign Institute and Department of Physics, SLAC National Accelerator Laboratory, University of Buffalo, University of North Carolina School of Medicine, and the Université de Lille in France.
The work was supported by National Institutes of Health grants, the NIMH Psychoactive Drug Screening Program, the National Science Foundation BioXFEL Science and Technology Center, and a postdoctoral fellowship from the Swedish Research Council, SLAC, supported by the U.S. Department of Energy’s Office of Science.