Neuropeptide Y Y1 receptor Structures Offer New Opportunities for Anti-obesity Drug Discovery

- Structures of human neuropeptide Y receptor Y₁R reveal drug recognition mechanisms

SHANGHAI, April 19, 2018 /PRNewswire/ -- Obesity is a major public health concern. Each year, millions of people die from obesity related diseases, such as diabetes and cardiovascular disease. Neuropeptide Y (NPY) is the most powerful stimulant of food intake and this effect is primarily mediated by the Y₁ receptor (Y₁R). Thus, Y₁R serves as an important drug target for many human diseases, such as obesity, type 2 diabetes and metabolic syndrome. However, the clinical usage of Y₁R ligands has been hampered by low potency and selectivity, poor brain penetration ability or lack of oral bioavailability.

Recently, scientists from Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences (CAS), in collaboration with several groups based in Germany, United States, China and Sweden, determined the high-resolution atomic structures of human Y₁R bound to two structurally diverse antagonists UR-MK299 and BMS-193885, providing a detailed molecular map of Y₁R and invaluable insights into understanding the pharmacology of NPY receptor. The study was recently published in Nature.

The Y₁R structures reveal, for the first time, the molecular details of an NPY receptor binding to its ligand at atomic level, and provide an accurate template for drug design targeting Y₁R. The structures combined with mutagenesis, ligand binding and signaling studies elucidate the binding modes of Y₁R to various antagonists and the molecular mechanisms of ligand selectivity in different NPY receptors. These findings offer new opportunities for anti-obesity drug discovery.

Based on the Y₁R structure, the researchers performed extensive studies including complementary mutagenesis, cell signaling, nuclear magnetic resonance, molecular docking and photo-crosslinking. The results provide insights into the binding behavior of the endogenous agonist NPY to Y₁R, and for the first time identified the binding site of NPY N terminus, which is critical for receptor selectivity, in Y₁R. These insights into Y₁R expand our understanding of NPY receptor signal transduction and lay a foundation for carrying out structure-based drug discovery that targets this physiologically important receptor.

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