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Structural analysis of the dual agonism at GLP-1R and GCGR

文献类型：期刊论文

作者Li, Yang8; Zhou, Qingtong7; Dai, Antao5,6; Zhao, Fenghui5,6; Chang, Rulue4; Ying, Tianlei8; Wu, Beili6; Yang, Dehua3,5,6; Wang, Ming-Wei1,2,3,6,8; Cong, Zhaotong7
刊名PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
出版日期2023-08-08
卷号120期号:33页码:12
关键词glucagon-like peptide-1 receptor glucagon receptor cryo-electron microscopy dual agonism
ISSN号0027-8424
DOI10.1073/pnas.2303696120
通讯作者Yang, Dehua(dhyang@simm.ac.cn) ; Wang, Ming-Wei(mwwang@simm.ac.cn) ; Cong, Zhaotong(congzt@fudan.edu.cn)
英文摘要Glucagon-like peptide-1 receptor (GLP-1R) and glucagon receptor (GCGR), two members of class B1 G protein-coupled receptors, play important roles in glucose homeostasis and energy metabolism. They share a high degree of sequence homology but have different functionalities. Unimolecular dual agonists of both receptors developed recently displayed better clinical efficacies than that of monotherapy. To study the underlying molecular mechanisms, we determined high-resolution cryo-electron microscopy structures of GLP-1R or GCGR in complex with heterotrimeric G(s) protein and three GLP-1R/ GCGR dual agonists including peptide 15, MEDI0382 (cotadutide) and SAR425899 with variable activating profiles at GLP-1R versus GCGR. Compared with related structures reported previously and supported by our published pharmacological data, key residues responsible for ligand recognition and dual agonism were identified. Analyses of peptide conformational features revealed a difference in side chain orientations within the first three residues, indicating that distinct engagements in the deep binding pocket are required to achieve receptor selectivity. The middle region recognizes extracellular loop 1 (ECL1), ECL2, and the top of transmembrane helix 1 (TM1) resulting in specific conformational changes of both ligand and receptor, especially the dual agonists reshaped ECL1 conformation of GLP-1R relative to that of GCGR, suggesting an important role of ECL1 interaction in executing dual agonism. Structural investigation of lipid modification showed a better interaction between lipid moiety of MEDI0382 and TM1-TM2 cleft, in line with its increased potency at GCGR than SAR425899. Together, the results provide insightful information for the design and development of improved therapeutics targeting these two receptors simultaneously.
WOS关键词GLUCAGON-LIKE PEPTIDE-1 ; PHARMACOLOGICAL ACTIONS ; CO-AGONISM ; RECEPTOR ; OXYNTOMODULIN ; REDUCTION ; OBESITY
资助项目National Natural Science Foundation of China[81872915] ; National Natural Science Foundation of China[82073904] ; National Natural Science Foundation of China[82273961] ; National Natural Science Foundation of China[32200576] ; National Natural Science Foundation of China[82273985] ; National Natural Science Foundation of China[82121005] ; National Natural Science Foundation of China[81973373] ; National Natural Science Foundation of China[21704064] ; Postdoctoral Science Foundation of China[2022M710806] ; Postdoctoral Innovative Talent Support Plan of China[BX20220070] ; National Science & Technology Major Project of China-Key New Drug Creation and Manufacturing Program[2018ZX09735-001] ; National Science & Technology Major Project of China-Key New Drug Creation and Manufacturing Program[2018ZX09711002-002-005] ; National Science & Technology Major Project of China-Key New Drug Creation and Manufacturing Program[2021ZD0203400] ; National Key Basic Research Program of China[2018YFA0507000] ; Hainan Provincial Major Science and Technology Project[ZDKJ2021028] ; Shanghai Municipality Science and Technology Development Fund[21JC1401600] ; Shanghai Municipality Science and Technology Development Fund[23XD1400900] ; cryo-EM data were collected at the Cryo-Electron Microscopy Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
WOS研究方向Science & Technology - Other Topics
语种英语
WOS记录号WOS:001194089800001
出版者NATL ACAD SCIENCES
源URL[http://119.78.100.183/handle/2S10ELR8/310535]  
专题中国科学院上海药物研究所
通讯作者Yang, Dehua; Wang, Ming-Wei; Cong, Zhaotong
作者单位1.Hainan Med Coll, Sch Pharm, Haikou 570228, Peoples R China
2.Univ Tokyo, Sch Sci, Dept Chem, Tokyo 113D0033, Japan
3.Res Ctr Deepsea Bioresources, Sanya 572025, Hainan, Peoples R China
4.Fudan Univ, Sch Pharm, Shanghai 201203, Peoples R China
5.Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, Shanghai 201203, Peoples R China
6.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Chem Biol, Shanghai 201203, Peoples R China
7.Fudan Univ, Sch Basic Med Sci, Dept Pharmacol, Shanghai 200032, Peoples R China
8.Fudan Univ, Shanghai Inst Infect Dis & Biosecur, Sch Basic Med Sci, Dept Med Microbiol & Parasitol, Shanghai 200032, Peoples R China
推荐引用方式
GB/T 7714		 Li, Yang,Zhou, Qingtong,Dai, Antao,et al. Structural analysis of the dual agonism at GLP-1R and GCGR[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,2023,120(33):12.
APA Li, Yang.,Zhou, Qingtong.,Dai, Antao.,Zhao, Fenghui.,Chang, Rulue.,...&Cong, Zhaotong.(2023).Structural analysis of the dual agonism at GLP-1R and GCGR.PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,120(33),12.
MLA Li, Yang,et al."Structural analysis of the dual agonism at GLP-1R and GCGR".PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 120.33(2023):12.

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来源：上海药物研究所

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