Gu Yi-Min, Yuan Qing-Ning, Li Xin, He Qian, Xu H Eric, Zhao Li-Hua
State Key Laboratory of Drug Research, Center for Structure and Function of Drug Targets, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
University of Chinese Academy of Sciences, Beijing, 100049, China.
Acta Pharmacol Sin. 2025 Aug 22. doi: 10.1038/s41401-025-01635-2.
The global obesity epidemic and its associated metabolic disorders urgently require more effective therapeutic interventions, particularly multi-pathway targeting therapies. Cagrilintide (Cagri), functioning as a dual amylin receptor (AMYRs) and calcitonin receptor (CTR) agonist (DACRA), demonstrates significant efficacy in obesity treatment, although its structural activation mechanism remains unclear. This study elucidates the non-selective activation mechanism by determining cryo-EM structures of Cagri bound to AMYR-G and CTR-G complexes. Cagri adopts similar "bypass" binding modes in both receptors, which is distinct from other existing DACRAs that primarily achieve extended half-life through N-terminal lipid modification. Key molecular features include the F23 residue anchoring the peptide at the receptor transmembrane (TM) bundle level and the micelle, an E14-R17 intramolecular salt bridge enhancing helical stability, and C-terminal P37 interaction with the receptor ECD. These features collectively enable non-specific binding and activation across different receptors. Both structural and functional analyses revealed Cagri's non-selective activation of G signaling pathways through CTR and AMYR. These findings provide a comprehensive structural framework for developing next-generation anti-obesity drugs based on dual receptor activation mechanisms.
全球肥胖流行及其相关代谢紊乱迫切需要更有效的治疗干预措施，特别是多途径靶向治疗。卡格列肽（Cagri）作为一种双重胰淀素受体（AMYRs）和降钙素受体（CTR）激动剂（DACRA），在肥胖治疗中显示出显著疗效，但其结构激活机制仍不清楚。本研究通过确定与AMYR-G和CTR-G复合物结合的卡格列肽的冷冻电镜结构，阐明了其非选择性激活机制。卡格列肽在两种受体中采用相似的“旁路”结合模式，这与其他现有的DACRAs不同，后者主要通过N端脂质修饰来延长半衰期。关键分子特征包括F23残基在受体跨膜（TM）束水平和胶束处锚定肽，E14-R17分子内盐桥增强螺旋稳定性，以及C端P37与受体胞外区（ECD）相互作用。这些特征共同实现了跨不同受体的非特异性结合和激活。结构和功能分析均揭示了卡格列肽通过CTR和AMYR对G信号通路的非选择性激活。这些发现为基于双受体激活机制开发下一代抗肥胖药物提供了全面的结构框架。
