Nature communicationsApr 9, 2025

How cagrilintide binds to calcitonin and amylin receptors, including its structure and behavior

GLP-1 Therapies Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Jan 20, 2026

Abstract

binds to active amylin and calcitonin receptors, demonstrating distinct conformational dynamics compared to other peptides.

Cagrilintide is a long-acting amylin and calcitonin receptor agonist under investigation for obesity treatment.
Binding structures of cagrilintide reveal an amylin-like binding mode at its target receptors.
Distinct conformational changes occur at calcitonin-family receptors when cagrilintide interacts, differing from other amylin-based peptides.
These unique dynamics may play a role in the clinical effectiveness of cagrilintide for obesity management.

Simplified

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 , 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 (AMYR, AMYR, AMYR) 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. 1 2 3

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Competing interests

Competing interests: P.M.S. is a co-founder and P.M.S. and D.W. are shareholders of Septerna Inc. P.M.S. and D.W. are co-founders and shareholders of Dacra Tx. T.G., K.R., B.B.-G., and S.R.-R. are employees and shareholders of Novo Nordisk. The work was funded, in part, by Novo Nordisk. All other authors declare no competing interests.

PubMed

How cagrilintide binds to calcitonin and amylin receptors, including its structure and behavior

Abstract

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