中国科学院机构知识库网格
Chinese Academy of Sciences Institutional Repositories Grid
首页 机构 成果 学者
  
  1. CAS IR Grid
  2. 上海药物研究所
  3. 中国科学院上海药物研究所
Structural insights into multiplexed pharmacological actions of tirzepatide and peptide 20 at the GIP, GLP-1 or glucagon receptors

文献类型：期刊论文

作者Zhao, Fenghui2,3; Zhou, Qingtong4; Cong, Zhaotong4; Hang, Kaini5; Zou, Xinyu6; Zhang, Chao5; Chen, Yan4; Dai, Antao7; Liang, Anyi6; Ming, Qianqian8,9
刊名NATURE COMMUNICATIONS
出版日期2022-02-25
卷号13期号:1页码:16
DOI10.1038/s41467-022-28683-0
通讯作者Yang, Dehua(dhyang@simm.ac.cn) ; Zhao, Lihua(zhaolihuawendy@simm.ac.cn) ; Xu, H. Eric(eric.xu@simm.ac.cn) ; Wang, Ming-Wei(mwwang@simm.ac.cn)
英文摘要Multi-targeting agonists at GIPR, GLP-1R or GCGR are pursued vigorously. Here, the authors report cryo-EM structures of tirzepatide-bound GIPR and GLP-1R, peptide 20-bound GIPR, GLP-1R and GCGR, revealing the molecular basis of their multiplexed pharmacological actions. 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.
WOS关键词CRYO-EM STRUCTURE ; DEPENDENT INSULINOTROPIC POLYPEPTIDE ; CRYSTAL-STRUCTURE ; CORRECTS OBESITY ; BIASED AGONISM ; PROTEIN ; ACTIVATION ; DYNAMICS ; MECHANISMS ; DISCOVERY
资助项目National Natural Science Foundation of China[81872915] ; National Natural Science Foundation of China[82073904] ; National Natural Science Foundation of China[32071203] ; National Natural Science Foundation of China[81922071] ; National Natural Science Foundation of China[81773792] ; National Natural Science Foundation of China[81973373] ; National Natural Science Foundation of China[21704064] ; National Science and Technology Major Project of China - Key New Drug Creation and Manufacturing Program[2018ZX09735-001] ; National Science and Technology Major Project of China - Key New Drug Creation and Manufacturing Program[2018ZX09711002-002-005] ; National Key Basic Research Program of China[2018YFA0507000] ; National Key Basic Research Program of China[2019YFA0508800] ; Ministry of Science and Technology of China[2018YFA0507002] ; Shanghai Municipal Science and Technology Major Project[2019SHZDZX02] ; Strategic Priority Research Program of Chinese Academy of Sciences[XDB37030103] ; Novo Nordisk-CAS Research Fund[NNCAS-2017-1-CC] ; Zhejiang Province Science Fund for Distinguished Young Scholars[LR19H310001] ; Fundamental Research Funds for Central Universities[2019XZZX001-01-06] ; Shanghai Science and Technology Development Funds[18ZR1447800] ; Shanghai Science and Technology Development Funds[18431907100] ; Young Innovator Association of CAS[2018325] ; SA-SIBS Scholarship Program
WOS研究方向Science & Technology - Other Topics
语种英语
出版者NATURE PORTFOLIO
WOS记录号WOS:000771121400002
源URL[http://119.78.100.183/handle/2S10ELR8/300030]  
专题中国科学院上海药物研究所
通讯作者Yang, Dehua; Zhao, Lihua; Xu, H. Eric; Wang, Ming-Wei
作者单位1.Univ Chinese Acad Sci, Beijing, Peoples R China
2.Fudan Univ, Sch Pharm, Shanghai, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai, Peoples R China
4.Fudan Univ, Sch Basic Med Sci, Dept Pharmacol, Shanghai, Peoples R China
5.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China
6.Huazhong Univ Sci & Technol, Sch Artificial Intelligence & Automat, Wuhan, Peoples R China
7.Chinese Acad Sci, Natl Ctr Drug Screening, Shanghai Inst Mat Med, Shanghai, Peoples R China
8.Zhejiang Univ, Sch Med, Sir Run Run Shaw Hosp, Dept Biophys, Hangzhou, Peoples R China
9.Zhejiang Univ, Sch Med, Sir Run Run Shaw Hosp, Dept Pathol, Hangzhou, Peoples R China
10.Res Ctr Deepsea Bioresources, Sanya, Hainan, Peoples R 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):16.
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),16.
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):16.

入库方式： OAI收割

来源：上海药物研究所

浏览0
下载0
收藏0
其他版本

除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。