{"id":"doi:10.1038/s41467-022-28683-0","kind":"article","title":"Structural insights into multiplexed pharmacological actions of tirzepatide and peptide 20 at the GIP, GLP-1 or glucagon receptors","authors":["Fenghui Zhao","Qingtong Zhou","Zhaotong Cong","Kaini Hang","Xinyu Zou","Chao Zhang","Yan Chen","Antao Dai","Anyi Liang","Qianqian Ming","Mu Wang","Li-Nan Chen","Peiyu Xu","Rulve Chang","Wenbo Feng","Tian Xia","Yan Zhang","Beili Wu","Dehua Yang","Lihua Zhao","H. Eric Xu","Ming‐Wei Wang"],"author_count":22,"year":2022,"published":"2022-02-25","venue":"Nature Communications","cited_by":149,"doi":"10.1038/s41467-022-28683-0","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1038/s41467-022-28683-0","archive_url":"https://space-kitty.com/papers/doi:10.1038/s41467-022-28683-0","updated":null,"pmid":"35217653","pmcid":"PMC8881610","openalex_id":"W4214764520","pdf_url":"https://www.nature.com/articles/s41467-022-28683-0.pdf","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.","abstract_license":"CC-BY (publisher license, via OpenAlex)","license":"cc-by","is_open_access":true,"retracted":false,"peer_reviewed":null,"categories":["Receptor Mechanisms and Signaling"],"details":null,"provenance":"openalex+europepmc","attribution":"Abstract of \"Structural insights into multiplexed pharmacological actions of tirzepatide and peptide 20 at the GIP, GLP-1 or glucagon receptors\" by Fenghui Zhao, Qingtong Zhou, Zhaotong Cong et al., https://doi.org/10.1038/s41467-022-28683-0, used under its Creative Commons Attribution license (CC-BY); markup removed, otherwise unmodified.","topics":[{"slug":"glp1-metabolic","name":"GLP-1 & Incretin Therapies","domain_slug":"medicine"}],"cited_in_dossiers":[]}