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

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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.

SOURCE Shanghai Institute of Materia Medica, Chinese Academy of Sciences