Highly Selective Y₄ Receptor Antagonist Binds in an Allosteric Binding Pocket

Human neuropeptide Y receptors (Y1R, Y2R, Y4R, and Y5R) belong to the superfamily of G protein-coupled receptors and play an important role in the regulation of food intake and energy metabolism. We identified and characterized the first selective Y4R allosteric antagonist (S)-VU0637120, an important step toward validating Y receptors as therapeutic targets for metabolic diseases. To obtain insight into the antagonistic mechanism of (S)-VU0637120, we conducted a variety of in vitro, ex vivo, and in silico studies. These studies revealed that (S)-VU0637120 selectively inhibits native Y4R function and binds in an allosteric site located below the binding pocket of the endogenous ligand pancreatic polypeptide in the core of the Y4R transmembrane domains. Taken together, our studies provide a first-of-its-kind tool for probing Y4R function and improve the general understanding of allosteric modulation, ultimately contributing to the rational development of allosteric modulators for peptide-activated G protein-coupled receptors (GPCRs).人类神经肽Y受体（Y1R、Y2R、Y4R及Y5R）属于G蛋白偶联受体（G protein-coupled receptors, GPCRs）超家族，在食物摄取与能量代谢调控中发挥关键作用。本研究鉴定并表征了首个选择性Y4R变构拮抗剂(S)-VU0637120，这是验证Y受体作为代谢疾病治疗靶点的重要进展。为阐明(S)-VU0637120的拮抗作用机制，本研究开展了一系列体外、离体及计算机模拟相关研究。结果显示，(S)-VU0637120可选择性抑制天然Y4R的功能，并结合于Y4R跨膜结构域核心区内、内源性配体胰多肽结合口袋下方的变构位点。综上，本研究提供了首个用于探究Y4R功能的专属工具，深化了学界对变构调控机制的整体认知，最终可为肽类激活型G蛋白偶联受体（GPCRs）的变构调节剂理性开发提供重要支撑。