@article{APS11433,
author = {Yi-min Gu and Qing-ning Yuan and Xin Li and Qian He and H. Eric Xu and Li-hua Zhao},
title = {Structural and mechanistic insights into dual activation of cagrilintide in amylin and calcitonin receptors},
journal = {Acta Pharmacologica Sinica},
volume = {47},
number = {1},
year = {2025},
keywords = {},
abstract = {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.},
issn = {1745-7254}, url = {http://www.chinaphar.com/article/view/11433}
}