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TitleStructural and mechanistic insights into dual activation of cagrilintide in amylin and calcitonin receptors.
Journal, issue, pagesActa Pharmacol Sin, Vol. 47, Issue 1, Page 162-172, Year 2026
Publish dateAug 22, 2025
AuthorsYi-Min Gu / Qing-Ning Yuan / Xin Li / Qian He / H Eric Xu / Li-Hua Zhao /
PubMed AbstractThe global obesity epidemic and its associated metabolic disorders urgently require more effective therapeutic interventions, particularly multi-pathway targeting therapies. Cagrilintide (Cagri), ...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.
External linksActa Pharmacol Sin / PubMed:40847076 / PubMed Central
MethodsEM (single particle)
Resolution3.06 - 3.62 Å
Structure data

EMDB-64557: A cryo_EM structure of Cagrilintide-CTR-Gs complex
Method: EM (single particle) / Resolution: 3.15 Å

EMDB-64558: A focused Cryo_EM structure of Cagrilintide-CTR-Gs complex
Method: EM (single particle) / Resolution: 3.15 Å

64560

9uwm

EMDB-64560, PDB-9uwm:
A combined cryo_EM structure of Cagrilintide-CTR-Gs complex
Method: EM (single particle) / Resolution: 3.1 Å

EMDB-64561: A focused Cryo_EM structure of Cagrilintide-AMY1R-Gs complex
Method: EM (single particle) / Resolution: 3.62 Å

EMDB-64562: A cryo_EM structure of Cagrilintide-AMY1R-Gs complex
Method: EM (single particle) / Resolution: 3.06 Å

64563

9uwq

EMDB-64563, PDB-9uwq:
A combined Cryo_EM structure of Cagrilintide-AMY1R-Gs complex
Method: EM (single particle) / Resolution: 3.1 Å

Source
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / GPCR / CTR / Cagrilintid / AMY1R

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