Abstact

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