EMD-31676
Cryo-EM structure of the GIPR/GLP-1R/GCGR triagonist peptide 20-bound human GCGR-Gs complex
EMD-31676
Single-particle3.5 Å
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Map released: 02/03/2022
Last modified: 16/03/2022
Sample Organism:
Homo sapiens,
synthetic construct,
Rattus norvegicus,
Bos taurus
Sample: Cryo-EM structure of the GIPR/GLP-1R/GCGR triagonist peptide 20-bound human GCGR-Gs complex
Fitted models: 7v35 (Avg. Q-score: 0.373)
Deposition Authors: Zhao F, Zhou QT, Cong ZT, Hang KN, Zou XY, Zhang C, Chen Y, Dai AT, Liang AY, Ming QQ, Wang M, Chen LN, Xu PY, Chang RL, Feng WB, Xia T, Zhang Y
,
Wu BL,
Yang DH,
Zhao LH,
Xu HE
,
Wang MW
Sample: Cryo-EM structure of the GIPR/GLP-1R/GCGR triagonist peptide 20-bound human GCGR-Gs complex
Fitted models: 7v35 (Avg. Q-score: 0.373)
Deposition Authors: Zhao F, Zhou QT, Cong ZT, Hang KN, Zou XY, Zhang C, Chen Y, Dai AT, Liang AY, Ming QQ, Wang M, Chen LN, Xu PY, Chang RL, Feng WB, Xia T, Zhang Y
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Structural insights into multiplexed pharmacological actions of tirzepatide and peptide 20 at the GIP, GLP-1 or glucagon receptors.
Zhao F,
Zhou Q,
Cong Z,
Hang K,
Zou X,
Zhang C,
Chen Y,
Dai A,
Liang A,
Ming Q,
Wang M,
Chen LN,
Xu P
,
Chang R,
Feng W,
Xia T,
Zhang Y
,
Wu B
,
Yang D
,
Zhao L
,
Xu HE
,
Wang MW
(2022) Nat Commun , 13 , 1057 - 1057
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(2022) Nat Commun , 13 , 1057 - 1057
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.
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.