Researchers have determined the molecular structure of the neuropeptide Y1 receptor (Y1R), a protein of central importance in food intake, which paves the way for new treatments for diseases such as obesity, type 2 diabetes and metabolic syndrome.
The research was carried out by scientists from Shanghai Institute of Materia Medica (SIMM) and Chinese Academy of Sciences (CAS) working in collaboration with groups based in Germany, the US, China and Sweden
Y1R is the primary mediator of neuropeptide Y (NPY), which is itself the most powerful stimulant of food intake. As such, Y1R has long been considered an important potential drug target for obesity-related diseases such as diabetes and cardiovascular disease. However, clinical use of Y1R ligands has been hindered by a lack of oral bioavailability, low potency and poor brain penetration ability.
The research team determined the high-resolution structures of human Y1R bound to UR-MK299 and BMS-193885, two structurally diverse antagonists. This enabled the researchers to form a detailed molecular map of Y1R and get an insight into the pharmacology of NPY receptor.
The Y1R structures revealed the molecular details of an NPY receptor binding to its ligand at atomic level, providing a template for a drug design targeting Y1R. The structures, combined with mutagenesis, ligand binding and signalling studies, elucidate the binding modes of Y1R to various antagonists and the molecular mechanisms of ligand selectivity in different NPY receptors.
Further studies were then conducted based on the Y1R structure, including complementary mutagenesis, cell signalling, nuclear magnetic resonance, molecular docking and photo-crosslinking. The findings offer greater insights into the binding behaviour of the endogenous agonist NPY to Y1R and identified the binding site of NPY N terminus in Y1R, which is of central importance in receptor selectivity.
These results lay a foundation for future structure-based drug developments targeting Y1R.
“The Y1R structures and our functional studies help us understand how this receptor binds to different types of ligands with molecular details,” research leader and SIMM professor Dr Beili Wu said.
“This can enable the development of new anti-obesity drugs with better selectivity and efficacy,”
Findings were published in Nature.
Globally, over 10% of people suffer from obesity – equating to 107.7 million children and 603.7 adults – with millions dying each year due to obesity-related diseases.
According to a 2017 study funded by the Bill and Melinda Gates Foundation, of the 20 largest countries in the world, the US had the worst rate of childhood obesity, with 13% of children now obese. Egypt had the highest rate of adult obesity at 35%.