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<p>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 AMY<sub>1</sub>R-G<sub>s</sub> and CTR-G<sub>s</sub> 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<sup>Cagri</sup> 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<sup>Cagri</sup> 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<sub>s</sub> signaling pathways through CTR and AMY<sub>1</sub>R. These findings provide a comprehensive structural framework for developing next-generation anti-obesity drugs based on dual receptor activation mechanisms.</p>

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Structural and mechanistic insights into dual activation of cagrilintide in amylin and calcitonin receptors

  • 期刊论文

  • 发表日期：

    2025年8月22日

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  • Yi-min Gu,
  • Qing-ning Yuan,
  • Xin Li,
  • Qian He,
  • H. Eric Xu,
  • Li-hua Zhao

摘要

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 AMY1R-Gs and CTR-Gs 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 F23Cagri 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 P37Cagri 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 Gs signaling pathways through CTR and AMY1R. These findings provide a comprehensive structural framework for developing next-generation anti-obesity drugs based on dual receptor activation mechanisms.