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A combined Cryo_EM structure of Cagrilintide-AMY1R-Gs complex
Structural highlights
FunctionGBB1_HUMAN Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems. The beta and gamma chains are required for the GTPase activity, for replacement of GDP by GTP, and for G protein-effector interaction.[1] Publication Abstract from PubMedThe 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. Structural and mechanistic insights into dual activation of cagrilintide in amylin and calcitonin receptors.,Gu YM, Yuan QN, Li X, He Q, Xu HE, Zhao LH Acta Pharmacol Sin. 2026 Jan;47(1):162-172. doi: 10.1038/s41401-025-01635-2. Epub , 2025 Aug 22. PMID:40847076[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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