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Structural insights into multiplexed pharmacological actions of tirzepatide and peptide 20 at the GIP, GLP-1 or glucagon receptors
- Source :
- Nature Communications. 13
- Publication Year :
- 2022
- Publisher :
- Springer Science and Business Media LLC, 2022.
-
Abstract
- Glucose homeostasis, regulated by glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1) and glucagon (GCG) is critical to human health. Several multi-targeting agonists at GIPR, GLP-1R or GCGR, developed to maximize metabolic benefits with reduced side-effects, are in clinical trials to treat type 2 diabetes and obesity. To elucidate the molecular mechanisms by which tirzepatide, a GIPR/GLP-1R dual agonist, and peptide 20, a GIPR/GLP-1R/GCGR triagonist, manifest their multiplexed pharmacological actions over monoagonists such as semaglutide, we determine cryo-electron microscopy structures of tirzepatide-bound GIPR and GLP-1R as well as peptide 20-bound GIPR, GLP-1R and GCGR. The structures reveal both common and unique features for the dual and triple agonism by illustrating key interactions of clinical relevance at the near-atomic level. Retention of glucagon function is required to achieve such an advantage over GLP-1 monotherapy. Our findings provide valuable insights into the structural basis of functional versatility of tirzepatide and peptide 20.
- Subjects :
- endocrine system
Multidisciplinary
Cryoelectron Microscopy
digestive, oral, and skin physiology
General Physics and Astronomy
Gastric Inhibitory Polypeptide
General Chemistry
Glucagon
Glucagon-Like Peptide-1 Receptor
General Biochemistry, Genetics and Molecular Biology
Receptors, G-Protein-Coupled
Glucose
Diabetes Mellitus, Type 2
Glucagon-Like Peptide 1
Receptors, Glucagon
Humans
Peptides
hormones, hormone substitutes, and hormone antagonists
Subjects
Details
- ISSN :
- 20411723
- Volume :
- 13
- Database :
- OpenAIRE
- Journal :
- Nature Communications
- Accession number :
- edsair.doi.dedup.....e3e0c0030a1922a97839a73f721f9807