Molecular insights into ago-allosteric modulation of the human glucagon-like peptide-1 receptor

doi:10.1038/s41467-021-24058-z

	Molecular insights into ago-allosteric modulation of the human glucagon-like peptide-1 receptor
	Cong, Zhaotong 1,2; Chen, Li-Nan 3; Ma, Honglei 2; Zhou, Qingtong 4; Zou, Xinyu 1,5; Ye, Chenyu 2; Dai, Antao 6; Liu, Qing 6; Huang, Wei 7; Sun, Xianqiang 7; Wang, Xi 2,8; Xu, Peiyu 2; Zhao, Lihua ; Xia, Tian 5; Zhong, Wenge 7; Yang, Dehua 2,6,8; Eric Xu, H.2,8; Zhang, Yan3,9,10,11,12 ; Wang, Ming-Wei1,2,4,6,8,12
	2021-06-18
发表期刊	NATURE COMMUNICATIONS
ISSN	2041-1723
卷号	12 期号:1
DOI	10.1038/s41467-021-24058-z
摘要	The glucagon-like peptide-1 (GLP-1) receptor is a validated drug target for metabolic disorders. Ago-allosteric modulators are capable of acting both as agonists on their own and as efficacy enhancers of orthosteric ligands. However, the molecular details of ago-allosterism remain elusive. Here, we report three cryo-electron microscopy structures of GLP-1R bound to (i) compound 2 (an ago-allosteric modulator); (ii) compound 2 and GLP-1; and (iii) compound 2 and LY3502970 (a small molecule agonist), all in complex with heterotrimeric G(s). The structures reveal that compound 2 is covalently bonded to C347 at the cytoplasmic end of TM6 and triggers its outward movement in cooperation with the ECD whose N terminus penetrates into the GLP-1 binding site. This allows compound 2 to execute positive allosteric modulation through enhancement of both agonist binding and G protein coupling. Our findings offer insights into the structural basis of ago-allosterism at GLP-1R and may aid the design of better therapeutics. The glucagon-like peptide-1 (GLP-1) receptor is a key regulator of glucose homeostasis and a drug target for type 2 diabetes but available GLP-1R agonists are suboptimal due to several side-effects. Here authors report the cryo-EM structure of GLP-1R bound to an ago-allosteric modulator in complex with heterotrimeric G(s) which offers insights into the molecular details of ago-allosterism.
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收录类别	SCIE
语种	英语
WOS研究方向	Science & Technology - Other Topics
WOS类目	Multidisciplinary Sciences
WOS记录号	WOS:000665038900031
出版者	NATURE RESEARCH
原始文献类型	Article
引用统计
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/127821
专题	物质科学与技术学院_公共科研平台_软纳米材料制备平台生命科学与技术学院_特聘教授组_王明伟组
通讯作者	Yang, Dehua; Eric Xu, H.; Zhang, Yan; Wang, Ming-Wei
作者单位	1.Fudan Univ, Sch Pharm, Shanghai, Peoples R China; 2.Shanghai Inst Mat Med, Chinese Acad Sci, CAS Key Lab Receptor Res, Shanghai, Peoples R China; 3.Zhejiang Univ, Dept Biophys, Sch Med, Dept Pathol Sir Run Run Shaw Hosp, Hangzhou, Peoples R China; 4.Fudan Univ, Sch Basic Med Sci, Shanghai, Peoples R China; 5.Huazhong Univ Sci & Technol, Sch Artificial Intelligence & Automat, Wuhan, Peoples R China; 6.Shanghai Inst Mat Med, Chinese Acad Sci, Natl Ctr Drug Screening, Shanghai, Peoples R China; 7.Qilu Regor Therapeutics Inc, Shanghai, Peoples R China; 8.Univ Chinese Acad Sci, Beijing, Peoples R China; 9.Zhejiang Univ Sch Med, MOE Frontier Sci Ctr, Brain Res & BrainMachine Integrat, Hangzhou, Peoples R China; 10.Key Lab Immun & Inflammatory Dis Zhejiang Prov, Hangzhou, Peoples R China; 11.Zhejiang Univ, Zhejiang Lab Syst & Precis Med, Med Ctr, Hangzhou, Peoples R China; 12.Shanghai Tech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China
通讯作者单位	生命科学与技术学院
推荐引用方式 GB/T 7714	Cong, Zhaotong,Chen, Li-Nan,Ma, Honglei,et al. Molecular insights into ago-allosteric modulation of the human glucagon-like peptide-1 receptor[J]. NATURE COMMUNICATIONS,2021,12(1).
APA	Cong, Zhaotong.,Chen, Li-Nan.,Ma, Honglei.,Zhou, Qingtong.,Zou, Xinyu.,...&Wang, Ming-Wei.(2021).Molecular insights into ago-allosteric modulation of the human glucagon-like peptide-1 receptor.NATURE COMMUNICATIONS,12(1).
MLA	Cong, Zhaotong,et al."Molecular insights into ago-allosteric modulation of the human glucagon-like peptide-1 receptor".NATURE COMMUNICATIONS 12.1(2021).