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Structural basis of peptidomimetic agonism revealed by small-molecule GLP-1R agonists Boc5 and WB4-24

文献类型：期刊论文

作者Cong, Zhaotong10; Zhou, Qingtong10; Li, Yang10; Chen, Li-Nan8,9; Zhang, Zi-Chen7; Liang, Anyi6; Liu, Qing5; Wu, Xiaoyan5; Dai, Antao5; Xia, Tian6
刊名PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
出版日期2022-05-17
卷号119期号:20页码:10
关键词glucagon-like peptide-1 receptor type 2 diabetes mellitus cryoelectron microscopy peptidomimetic agonism
ISSN号0027-8424
DOI10.1073/pnas.2200155119
通讯作者Yang, Dehua(dhyang@simm.ac.cn) ; Wang, Ming-Wei(mwwang@simm.ac.cn)
英文摘要Glucagon-like peptide-1 receptor (GLP-1R) agonists are effective in treating type 2 diabetes and obesity with proven cardiovascular benefits. However, most of these agonists are peptides and require subcutaneous injection except for orally available semaglutide. Boc5 was identified as the first orthosteric nonpeptidic agonist of GLP-1R that mimics a broad spectrum of bioactivities of GLP-1 in vitro and in vivo. Here, we report the cryoelectron microscopy structures of Boc5 and its analog WB4-24 in complex with the human GLP-1R and G, protein. Bound to the extracellular domain, extracellular loop 2, and transmembrane (TM) helices 1, 2, 3, and 7, one arm of both compounds was inserted deeply into the bottom of the orthosteric binding pocket that is usually accessible by peptidic agonists, thereby partially overlapping with the residues A8 to D15 in GLP-1. The other three arms, meanwhile, extended to the TM1-TM7, TM1-TM2, and TM2-TM3 clefts, showing an interaction feature substantially similar to the previously known small-molecule agonist LY3502970. Such a unique binding mode creates a distinct conformation that confers both peptidomimetic agonism and biased signaling induced by nonpeptidic modulators at GLP-1R. Further, the conformational difference between Boc5 and WB4-24, two closed related compounds, provides a structural framework for fine-tuning of pharmacological efficacy in the development of future small-molecule therapeutics targeting GLP-1R.
WOS关键词PEPTIDE-1 RECEPTOR ; GLUCAGON ; ACTIVATION ; FAMILY
资助项目National Natural Science Foundation of China[81872915] ; National Natural Science Foundation of China[82073904] ; National Natural Science Foundation of China[82121005] ; National Natural Science Foundation of China[81973373] ; National Natural Science Foundation of China[21704064] ; 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] ; Novo Nordisk-CAS Research Fund[NNCAS-2017-1-CC] ; SA-SIBS Scholarship Program ; 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:000841330100012
出版者NATL ACAD SCIENCES
源URL[http://119.78.100.183/handle/2S10ELR8/302326]  
专题中国科学院上海药物研究所
通讯作者Yang, Dehua; Wang, Ming-Wei
作者单位1.Univ Tokyo, Sch Sci, Dept Chem, Tokyo 1130033, Japan
2.Res Ctr Deepsea Bioresources, Dept Bioact Screening, Sanya 572025, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China
4.Univ Chinese Acad Sci, Sch Grad Studies, Beijing 100049, Peoples R China
5.Chinese Acad Sci, Natl Ctr Drug Screening, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
6.Huazhong Univ Sci & Technol, Sch Artificial Intelligence & Automat, Wuhan 430074, Peoples R China
7.Fudan Univ, Sch Pharm, Shanghai 201203, Peoples R China
8.Zhejiang Univ, Sir Run Run Shaw Hosp, Dept Pathol, Sch Med, Hangzhou 310058, Peoples R China
9.Zhejiang Univ, Sir Run Run Shaw Hosp, Dept Biophys, Sch Med, Hangzhou 310058, Peoples R China
10.Fudan Univ, Sch Basic Med Sci, Dept Pharmacol, Shanghai 200032, Peoples R China
推荐引用方式
GB/T 7714		 Cong, Zhaotong,Zhou, Qingtong,Li, Yang,et al. Structural basis of peptidomimetic agonism revealed by small-molecule GLP-1R agonists Boc5 and WB4-24[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,2022,119(20):10.
APA Cong, Zhaotong.,Zhou, Qingtong.,Li, Yang.,Chen, Li-Nan.,Zhang, Zi-Chen.,...&Wang, Ming-Wei.(2022).Structural basis of peptidomimetic agonism revealed by small-molecule GLP-1R agonists Boc5 and WB4-24.PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,119(20),10.
MLA Cong, Zhaotong,et al."Structural basis of peptidomimetic agonism revealed by small-molecule GLP-1R agonists Boc5 and WB4-24".PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 119.20(2022):10.

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来源：上海药物研究所

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