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

doi:10.1021/acschembio.1c00552

	Allosteric Modulators Enhancing GLP-1 Binding to GLP-1R via a Transmembrane Site
	Wang, Jiang 1,2,3,4; Yang, Dehua 1,2; Cheng, Xi 1,2,4; Yang, Linlin 5; Wang, Zhaohui 1,2; Dai, Antao 1,2; Cai, Xiaoqing 1,2; Zhang, Chao6 ; Yuliantie, Elita 1,2; Liu, Qiaofeng 7; Jiang, Hualiang 1,2,3,4; Liu, Hong 1,2,3,4; Wang, Ming-Wei 1,2,3,8; Yang, Huaiyu 9
	2021-11-19
发表期刊	ACS CHEMICAL BIOLOGY (IF:3.5[JCR-2023],3.9[5-Year])
ISSN	1554-8929
EISSN	1554-8937
卷号	16 期号:11
发表状态	已发表
DOI	10.1021/acschembio.1c00552
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.
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收录类别	SCI ; SCIE
语种	英语
资助项目	National Science and Technology Major Project of China-Key New Drug Creation and Manufacturing Program["2018ZX09735-001","2018ZX09711002-002-003","2018ZX09711002-002-005"] ; National Natural Science Foundation[81872915,82073904,81620108027,21632008,21877118,81773792,81973373,82121005] ; Youth Innovation Promotion Association of CAS[2018319] ; National Key Research and Development Program of China[2018YFA0508100] ; China Postdoctoral Science Foundation[2017M622365]
WOS研究方向	Biochemistry & Molecular Biology
WOS类目	Biochemistry & Molecular Biology
WOS记录号	WOS:000726640700002
出版者	AMER CHEMICAL SOC
引用统计	正在获取...
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/135620
专题	生命科学与技术学院_硕士生
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.Zhengzhou Univ, Sch Basic Med Sci, Dept Pharmacol, Zhengzhou 450001, Peoples R China 6.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China 7.Fudan Univ, Sch Pharm, Shanghai 201203, Peoples R China 8.Fudan Univ, Sch Basic Med Sci, Dept Pharmacol, Shanghai 200032, Peoples R China 9.East China Normal Univ, Sch Life Sci, Inst Biomed Sci, Shanghai Key Lab Regulatory Biol, Shanghai 200241, 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).
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).
MLA	Wang, Jiang,et al."Allosteric Modulators Enhancing GLP-1 Binding to GLP-1R via a Transmembrane Site".ACS CHEMICAL BIOLOGY 16.11(2021).