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<p>The neuropeptide Y<sub>4</sub> receptor (Y<sub>4</sub>R) and its endogenous ligand pancreatic polypeptide (PP) are primarily involved in the regulation of satiety and energy balance and present relevant pharmacological targets. We characterized the novel Y<sub>4</sub>R positive allosteric modulator C1 that enhances Y<sub>4</sub>R G-protein signaling, ligand binding, and arrestin-3 recruitment to Y<sub>4</sub>R. Comparison with a close analog revealed the structural importance of an ethyl acetate moiety for Y<sub>4</sub>R affinity and PAM activity at the G-protein pathway. C1 shows a high selectivity for the Y<sub>4</sub>R, while signaling of the related subtypes Y<sub>1</sub>R, Y<sub>2</sub>R, and Y<sub>5</sub>R is not affected. Y<sub>4</sub>R G-protein signaling is even potentiated by the low-affinity agonists neuropeptide Y and peptide YY. Binding affinity of the endogenous ligands to Y<sub>4</sub>R is enhanced by C1, indicating a stabilization of the ligand-bound Y<sub>4</sub>R conformation. Using Y<sub>4</sub>R/Y<sub>1</sub>R chimera, important Y<sub>4</sub>R domains for C1 activity were identified. Single point mutagenesis and computational docking pinpointed hot-spot residues at Y<sub>4</sub>R important for stabilizing the active ligand-bound conformation.</p>

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The pathway-independent positive allosteric modulator C1 allows for the identification of active Y4 receptor relevant positions

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月13日

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  • Corinna Schüß,
  • Oanh Vu,
  • Tim Pelczyk,
  • Mario Schubert,
  • Yu Du,
  • Jan Stichel,
  • C. David Weaver,
  • Jens Meiler,
  • Annette G. Beck-Sickinger

摘要

The neuropeptide Y4 receptor (Y4R) and its endogenous ligand pancreatic polypeptide (PP) are primarily involved in the regulation of satiety and energy balance and present relevant pharmacological targets. We characterized the novel Y4R positive allosteric modulator C1 that enhances Y4R G-protein signaling, ligand binding, and arrestin-3 recruitment to Y4R. Comparison with a close analog revealed the structural importance of an ethyl acetate moiety for Y4R affinity and PAM activity at the G-protein pathway. C1 shows a high selectivity for the Y4R, while signaling of the related subtypes Y1R, Y2R, and Y5R is not affected. Y4R G-protein signaling is even potentiated by the low-affinity agonists neuropeptide Y and peptide YY. Binding affinity of the endogenous ligands to Y4R is enhanced by C1, indicating a stabilization of the ligand-bound Y4R conformation. Using Y4R/Y1R chimera, important Y4R domains for C1 activity were identified. Single point mutagenesis and computational docking pinpointed hot-spot residues at Y4R important for stabilizing the active ligand-bound conformation.