Structural and dynamic features of cagrilintide binding to calcitonin and amylin receptors

Jianjun Cao; Matthew J. Belousoff; Rachel M. Johnson; Peter Keov; Zamara Mariam; Giuseppe Deganutti; George Christopoulos; Caroline A. Hick; Steffen Reedtz-Runge; Tine Glendorf; Borja Ballarín-González; Kirsten Raun; Charles Bayly-Jones; Denise Wootten; Patrick M. Sexton

doi:10.1038/s41467-025-58680-y

Structural and dynamic features of cagrilintide binding to calcitonin and amylin receptors

Jianjun Cao, Matthew J. Belousoff, Rachel M. Johnson, Peter Keov, Zamara Mariam, Giuseppe Deganutti, George Christopoulos, Caroline A. Hick, Steffen Reedtz-Runge, Tine Glendorf, Borja Ballarín-González, Kirsten Raun, Charles Bayly-Jones, Denise Wootten, Patrick M. Sexton

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Abstract

Obesity is a major and increasingly prevalent chronic metabolic disease with numerous comorbidities. While recent incretin-based therapies have provided pharmaceutical inroads into treatment of obesity, there remains an ongoing need for additional medicines with distinct modes of action as independent or complementary therapeutics. Among the most promising candidates, supported by phase 1 and 2 clinical trials, is cagrilintide, a long-acting amylin and calcitonin receptor agonist. As such, understanding how cagrilintide functionally engages target receptors is critical for future development of this target class. Here, we determine structures of cagrilintide bound to Gs-coupled, active, amylin receptors (AMY1R, AMY2R, AMY3R) and calcitonin receptor (CTR) and compare cagrilintide interactions and the dynamics of receptor complexes with previously reported structures of receptors bound to rat amylin, salmon calcitonin or recently developed amylin-based peptides. These data reveal that cagrilintide has an amylin-like binding mode but, compared to other peptides, induces distinct conformational dynamics at calcitonin-family receptors that could contribute to its clinical efficacy.

Original language	English
Article number	3389
Pages (from-to)	3389
Number of pages	1
Journal	Nature Communications
Volume	16
Issue number	1
Early online date	10 Apr 2025
DOIs	https://doi.org/10.1038/s41467-025-58680-y
Publication status	E-pub ahead of print - 10 Apr 2025

Bibliographical note

Publisher Copyright:
© The Author(s) 2025.

Funding

P.M.S. received a NHMRC Senior Principal Research Fellowship (grant ID: 1154434), a NHMRC Leadership grant (ID: 2025694), and an ARC Discovery Project grant (DP210101504). D.W. received a NHMRC Senior Research Fellowship (grant ID: 1155302) and a NHMRC Leadership grant (ID: 2026300). P.M.S. is Director and D.W. is the Monash University Node leader of the ARC Industrial Transformation Training Centre for Cryo-electron Microscopy of Membrane Proteins (CCeMMP) (grant ID: IC200100052), which received support from Novo Nordisk for the current project. The work was supported by the Monash University Ramaciotti Centre for Cryo-Electron Microscopy, the Bio21 Ian Holmes Imaging Centre (The University of Melbourne) and the Monash eResearch capabilities, including\u00A0M3 High-performance computing. Figures were created with UCSF Chimera and ChimeraX, developed by the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco, with support from National Institutes of Health R01-GM129325 and the Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases. P.M.S. received a NHMRC Senior Principal Research Fellowship (grant ID: 1154434), a NHMRC Leadership grant (ID: 2025694), and an ARC Discovery Project grant (DP210101504). D.W. received a NHMRC Senior Research Fellowship (grant ID: 1155302) and a NHMRC Leadership grant (ID: 2026300). P.M.S. is Director and D.W. is the Monash University Node leader of the ARC Industrial Transformation Training Centre for Cryo-electron Microscopy of Membrane Proteins (CCeMMP) (grant ID: IC200100052), which received support from Novo Nordisk for the current project. The work was supported by the Monash University Ramaciotti Centre for Cryo-Electron Microscopy, the Bio21 Ian Holmes Imaging Centre (The University of Melbourne) and the Monash eResearch capabilities, including M3 High-performance computing. Figures were created with UCSF Chimera and ChimeraX, developed by the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco, with support from National Institutes of Health R01-GM129325 and the Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases.

Funders	Funder number
Novo Nordisk
University of Melbourne
Monash University
National Institute of Allergy and Infectious Diseases
Australian Research Council	DP210101504, 1155302, 2026300, IC200100052
Australian Research Council
National Institutes of Health	R01-GM129325
National Institutes of Health
National Health and Medical Research Council	1154434, 2025694
National Health and Medical Research Council

Keywords

Amylin Receptor Agonists
Animals
Calcitonin
Crystallography, X-Ray
Humans
Islet Amyloid Polypeptide
Peptides
Protein Binding
Rats
Receptors, Calcitonin
Receptors, Islet Amyloid Polypeptide

ASJC Scopus subject areas

General Chemistry
General Biochemistry,Genetics and Molecular Biology
General Physics and Astronomy

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Cao, J., Belousoff, M. J., Johnson, R. M., Keov, P., Mariam, Z., Deganutti, G., Christopoulos, G., Hick, C. A., Reedtz-Runge, S., Glendorf, T., Ballarín-González, B., Raun, K., Bayly-Jones, C., Wootten, D., & Sexton, P. M. (2025). Structural and dynamic features of cagrilintide binding to calcitonin and amylin receptors. Nature Communications, 16(1), 3389. Article 3389. Advance online publication. https://doi.org/10.1038/s41467-025-58680-y

Cao, J, Belousoff, MJ, Johnson, RM, Keov, P, Mariam, Z , Deganutti, G, Christopoulos, G, Hick, CA, Reedtz-Runge, S, Glendorf, T, Ballarín-González, B, Raun, K, Bayly-Jones, C, Wootten, D & Sexton, PM 2025, 'Structural and dynamic features of cagrilintide binding to calcitonin and amylin receptors', Nature Communications, vol. 16, no. 1, 3389, pp. 3389. https://doi.org/10.1038/s41467-025-58680-y

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AU - Mariam, Zamara

AU - Deganutti, Giuseppe

AU - Christopoulos, George

AU - Hick, Caroline A.

AU - Reedtz-Runge, Steffen

AU - Glendorf, Tine

AU - Ballarín-González, Borja

AU - Raun, Kirsten

AU - Bayly-Jones, Charles

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N2 - Obesity is a major and increasingly prevalent chronic metabolic disease with numerous comorbidities. While recent incretin-based therapies have provided pharmaceutical inroads into treatment of obesity, there remains an ongoing need for additional medicines with distinct modes of action as independent or complementary therapeutics. Among the most promising candidates, supported by phase 1 and 2 clinical trials, is cagrilintide, a long-acting amylin and calcitonin receptor agonist. As such, understanding how cagrilintide functionally engages target receptors is critical for future development of this target class. Here, we determine structures of cagrilintide bound to Gs-coupled, active, amylin receptors (AMY1R, AMY2R, AMY3R) and calcitonin receptor (CTR) and compare cagrilintide interactions and the dynamics of receptor complexes with previously reported structures of receptors bound to rat amylin, salmon calcitonin or recently developed amylin-based peptides. These data reveal that cagrilintide has an amylin-like binding mode but, compared to other peptides, induces distinct conformational dynamics at calcitonin-family receptors that could contribute to its clinical efficacy.

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Structural and dynamic features of cagrilintide binding to calcitonin and amylin receptors

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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