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Allosteric Modulators Enhancing GLP-1 Binding to GLP-1R via a Transmembrane Site

文献类型：期刊论文

作者Wang, Jiang1,2,3,4; Yang, Dehua1,2; Cheng, Xi1,2,4; Yang, Linlin6; Wang, Zhaohui1,2; Dai, Antao1,2; Cai, Xiaoqing1,2; Zhang, Chao7; Yuliantie, Elita1,2; Liu, Qiaofeng8
刊名ACS CHEMICAL BIOLOGY
出版日期2021-11-19
卷号16期号:11页码:2444-2452
ISSN号1554-8929
DOI10.1021/acschembio.1c00552
通讯作者Liu, Hong(hliu@simm.ac.cn) ; Wang, Ming-Wei(mwwang@simm.ac.cn) ; Yang, Huaiyu(hyyang@bio.ecnu.edu.cn)
英文摘要The glucagon-like peptide-1 receptor (GLP-1R) is a well-established drug target for the treatment of type II diabetes. The development of small-molecule positive allosteric modulators (PAMs) of GLP-1R is a promising therapeutic strategy. Here, we report the discovery and characterization of PAMs with distinct chemotypes, binding to a cryptic pocket formed by the cytoplasmic half of TM3, TM5, and TM6. Molecular dynamic simulations and mutagenesis studies indicate that the PAM enlarges the orthosteric pocket to facilitate GLP-1 binding. Further signaling assays characterized their probe-dependent signaling profiles. Our findings provide mechanistic insights into fine-tuning GLP-1R via this allosteric pocket and open up new avenues to design small-molecule drugs for class B G-protein-coupled receptors.
WOS关键词GLUCAGON-LIKE PEPTIDE-1 ; INSULIN-SECRETION ; RECEPTOR ; ACTIVATION ; TYPE-2 ; AGONISTS ; DISCOVERY
资助项目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[2018ZX09711002-002-003] ; National Science and Technology Major Project of China-Key New Drug Creation and Manufacturing Program[2018ZX09711002-002-005] ; National Natural Science Foundation[81872915] ; National Natural Science Foundation[82073904] ; National Natural Science Foundation[81620108027] ; National Natural Science Foundation[21632008] ; National Natural Science Foundation[21877118] ; National Natural Science Foundation[81773792] ; National Natural Science Foundation[81973373] ; National Natural Science Foundation[82121005] ; Youth Innovation Promotion Association of CAS[2018319] ; National Key Research and Development Program of China[2018YFA0508100] ; China Postdoctoral Science Foundation[2017M622365] ; Fundamental Research Funds for the Central Universities ; ECNU
WOS研究方向Biochemistry & Molecular Biology
语种英语
WOS记录号WOS:000726640700002
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/299045]  
专题新药研究国家重点实验室
通讯作者Liu, Hong; Wang, Ming-Wei; Yang, Huaiyu
作者单位1.Chinese Acad Sci, Natl Ctr Drug Screening, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
2.Chinese Acad Sci, CAS Key Lab Receptor Res, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
4.Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China
5.East China Normal Univ, Sch Life Sci, Inst Biomed Sci, Shanghai Key Lab Regulatory Biol, Shanghai 200241, Peoples R China
6.Zhengzhou Univ, Sch Basic Med Sci, Dept Pharmacol, Zhengzhou 450001, Peoples R China
7.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China
8.Fudan Univ, Sch Pharm, Shanghai 201203, Peoples R China
9.Fudan Univ, Sch Basic Med Sci, Dept Pharmacol, Shanghai 200032, Peoples R China
推荐引用方式
GB/T 7714		 Wang, Jiang,Yang, Dehua,Cheng, Xi,et al. Allosteric Modulators Enhancing GLP-1 Binding to GLP-1R via a Transmembrane Site[J]. ACS CHEMICAL BIOLOGY,2021,16(11):2444-2452.
APA Wang, Jiang.,Yang, Dehua.,Cheng, Xi.,Yang, Linlin.,Wang, Zhaohui.,...&Yang, Huaiyu.(2021).Allosteric Modulators Enhancing GLP-1 Binding to GLP-1R via a Transmembrane Site.ACS CHEMICAL BIOLOGY,16(11),2444-2452.
MLA Wang, Jiang,et al."Allosteric Modulators Enhancing GLP-1 Binding to GLP-1R via a Transmembrane Site".ACS CHEMICAL BIOLOGY 16.11(2021):2444-2452.

入库方式： OAI收割

来源：上海药物研究所

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