Structural and dynamic features of cagrilintide binding to calcitonin and amylin receptors
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...
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Nature Portfolio
2025-04-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-58680-y |
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| author | 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 |
| author_facet | 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 |
| author_sort | Jianjun Cao |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-23930f4748734b21988f991fa9614f8f |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-23930f4748734b21988f991fa9614f8f2025-08-20T02:17:01ZengNature PortfolioNature Communications2041-17232025-04-0116111510.1038/s41467-025-58680-yStructural and dynamic features of cagrilintide binding to calcitonin and amylin receptorsJianjun Cao0Matthew J. Belousoff1Rachel M. Johnson2Peter Keov3Zamara Mariam4Giuseppe Deganutti5George Christopoulos6Caroline A. Hick7Steffen Reedtz-Runge8Tine Glendorf9Borja Ballarín-González10Kirsten Raun11Charles Bayly-Jones12Denise Wootten13Patrick M. Sexton14Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash UniversityDrug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash UniversityDrug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash UniversityDrug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash UniversityCentre for Health and Life Sciences, Coventry UniversityCentre for Health and Life Sciences, Coventry UniversityDrug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash UniversityDrug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash UniversityResearch & Early Development, Novo NordiskResearch & Early Development, Novo NordiskResearch & Early Development, Novo NordiskResearch & Early Development, Novo NordiskARC Centre for Cryo-electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Monash UniversityDrug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash UniversityDrug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash UniversityAbstract 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.https://doi.org/10.1038/s41467-025-58680-y |
| spellingShingle | 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 Structural and dynamic features of cagrilintide binding to calcitonin and amylin receptors Nature Communications |
| title | Structural and dynamic features of cagrilintide binding to calcitonin and amylin receptors |
| title_full | Structural and dynamic features of cagrilintide binding to calcitonin and amylin receptors |
| title_fullStr | Structural and dynamic features of cagrilintide binding to calcitonin and amylin receptors |
| title_full_unstemmed | Structural and dynamic features of cagrilintide binding to calcitonin and amylin receptors |
| title_short | Structural and dynamic features of cagrilintide binding to calcitonin and amylin receptors |
| title_sort | structural and dynamic features of cagrilintide binding to calcitonin and amylin receptors |
| url | https://doi.org/10.1038/s41467-025-58680-y |
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