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

Acta Pharmacologica Sinica (2025)Cite this article

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.

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Fig. 1: Structural and functional characterization of Cagri interactions with CTR and AMY1R receptors.
Fig. 2: Molecular mechanism of Cagri recognition by CTR.
Fig. 3: Molecular mechanism of Cagri recognition by AMY1R.
Fig. 4: Structural basis of Cagri’s non-selective activation of CTR and AMY1R.
Fig. 5: Activation mechanism of AMY1R.

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Data availability

The atomic coordinates for the Cagri‒CTR‒Gs and Cagri‒AMY1R‒Gs complexes have been deposited in the Protein Data Bank (PDB) under accession codes 9UWM and 9UWQ, respectively. Cryo-EM maps have been deposited in the Electron Microscopy Data Bank under the following accession codes: for the Cagri‒CTR‒Gs complex, EMD-64557 (raw map), EMD-64558 (receptor-focused refinement map), and EMD-64560 (composite map); for the Cagri‒AMY1R‒Gs complex, EMD-64562 (raw map), EMD-64561 (receptor-focused refinement map), and EMD-64563 (composite map).

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Acknowledgements

We acknowledge the use of cryo-EM facilities at the Advanced Center for Electron Microscopy, Shanghai Institute of Materia Medica, Chinese Academy of Sciences. We are grateful to WH and KW for technical assistance with data collection. This work was supported by the National Natural Science Foundation of China (32371255 and 32071203 to LHZ, 32130022 and 82121005 to HEX, 82404881 to QNY); the Natural Science Foundation of Shanghai (23ZR1475200 to LHZ); the National Key R&D Program of China (2022YFC2703105 to HEX, 2019YFA0904200); the CAS Strategic Priority Research Program (XDB37030103 to HEX); the Shanghai Municipal Science and Technology Major Project (2019SHZDZX02 to HEX); the Young Innovator Association of CAS (Y2022078 to LHZ); the Lingang Laboratory (LG-GG-202204-01 to HEX); the State Key Laboratory of Drug Research (SKLDR-2023-TT-04 to HEX).

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Author notes

  1. These authors contributed equally: Yi-min Gu, Qing-ning Yuan, Xin Li

Authors and Affiliations

  1. State Key Laboratory of Drug Research, Center for Structure and Function of Drug Targets, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China

    Yi-min Gu, Xin Li, Qian He & H. Eric Xu

  2. University of Chinese Academy of Sciences, Beijing, 100049, China

    Yi-min Gu, Xin Li, Qian He & H. Eric Xu

  3. Research Center for Medicinal Structural Biology, National Research Center for Translational Medicine at Shanghai, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China

    Qing-ning Yuan & Li-hua Zhao

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  1. Yi-min Gu
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  4. Qian He
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Contributions

YMG designed the expression constructs and purified the protein complex under supervision of LHZ and HEX; LHZ and QNY prepared the grids. QNY performed cryo-EM data processing and model building. YMG constructed all the mutated plasmids and conducted functional studies under supervision of LHZ; XL carried out functional experiments supervised by LHZ; YMG, QH, and LHZ analyzed the structures. YMG prepared the figures and contributed to manuscript writing. All authors discussed and commented on the manuscript. LHZ and HEX wrote, revised, and finalized the manuscript, and jointly conceived, designed, and supervised the project.

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Correspondence to H. Eric Xu or Li-hua Zhao.

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Gu, Ym., Yuan, Qn., Li, X. et al. Structural and mechanistic insights into dual activation of cagrilintide in amylin and calcitonin receptors. Acta Pharmacol Sin (2025). https://doi.org/10.1038/s41401-025-01635-2

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