Structural insights into multiplexed pharmacological actions of tirzepatide and peptide 20 at the GIP, GLP-1 or glucagon receptors

doi:10.1038/s41467-022-28683-0

	Structural insights into multiplexed pharmacological actions of tirzepatide and peptide 20 at the GIP, GLP-1 or glucagon receptors
	Zhao, Fenghui 1,2; Zhou, Qingtong 3; Cong, Zhaotong 3; Hang, Kaini4 ; Zou, Xinyu 5; Zhang, Chao4 ; Chen, Yan 3; Dai, Antao 6; Liang, Anyi 5; Ming, Qianqian 7; Wang, Mu4 ; Chen, Li Nan 7; Xu, Peiyu 2; Chang, Rulve 1; Feng, Wenbo 3; Xia, Tian 5; Zhang, Yan 7; Wu, Beili2,4,8 ; Yang, Dehua 2,6,8,9; Zhao, Lihua 2,8; Xu, H. Eric 2,8; Wang, Ming Wei1,2,3,4,6,8,9
	2022-02-25
发表期刊	NATURE COMMUNICATIONS
EISSN	2041-1723
卷号	13 期号:1
发表状态	已发表
DOI	10.1038/s41467-022-28683-0
摘要	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.
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收录类别	SCIE
语种	英语
Scopus 记录号	2-s2.0-85125529681
来源库	Scopus
引用统计
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/161451
专题	生命科学与技术学院_博士生生命科学与技术学院_特聘教授组_王明伟组生命科学与技术学院_特聘教授组_吴蓓丽组生命科学与技术学院_硕士生
通讯作者	Yang, Dehua; Zhao, Lihua; Xu, H. Eric
作者单位	1.School of Pharmacy,Fudan University,Shanghai,China 2.The CAS Key Laboratory of Receptor Research,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai,China 3.Department of Pharmacology,School of Basic Medical Sciences,Fudan University,Shanghai,China 4.School of Life Science and Technology,ShanghaiTech University,Shanghai,China 5.School of Artificial Intelligence and Automation,Huazhong University of Science and Technology,Wuhan,China 6.The National Center for Drug Screening,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai,China 7.Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital,Zhejiang University School of Medicine,Hangzhou,China 8.University of Chinese Academy of Sciences,Beijing,China 9.Research Center for Deepsea Bioresources,Sanya,Hainan,China
推荐引用方式 GB/T 7714	Zhao, Fenghui,Zhou, Qingtong,Cong, Zhaotong,et al. Structural insights into multiplexed pharmacological actions of tirzepatide and peptide 20 at the GIP, GLP-1 or glucagon receptors[J]. NATURE COMMUNICATIONS,2022,13(1).
APA	Zhao, Fenghui.,Zhou, Qingtong.,Cong, Zhaotong.,Hang, Kaini.,Zou, Xinyu.,...&Wang, Ming Wei.(2022).Structural insights into multiplexed pharmacological actions of tirzepatide and peptide 20 at the GIP, GLP-1 or glucagon receptors.NATURE COMMUNICATIONS,13(1).
MLA	Zhao, Fenghui,et al."Structural insights into multiplexed pharmacological actions of tirzepatide and peptide 20 at the GIP, GLP-1 or glucagon receptors".NATURE COMMUNICATIONS 13.1(2022).