Conformational Dynamics of the Activated GLP-1 Receptor-Gs Complex Revealed by Cross-Linking Mass Spectrometry and Integrative Structure Modeling

doi:10.1021/acscentsci.3c00063

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	Conformational Dynamics of the Activated GLP-1 Receptor-Gs Complex Revealed by Cross-Linking Mass Spectrometry and Integrative Structure Modeling
	Yuan, Shijia1,2,3 ; Xia, Lisha1,2,3 ; Wang, Chenxi1,2,3 ; Wu, Fan 4; Zhang, Bingjie1 ; Pan, Chen 5; Fan, Zhiran 6; Lei, Xiaoguang 7; Stevens, Raymond C.1,2,4 ; Sali, Andrej 8,9,10; Sun, Liping1 ; Shui, Wenqing1,2
	2023
发表期刊	ACS CENTRAL SCIENCE (IF:12.7[JCR-2023],15.8[5-Year])
ISSN	2374-7943
EISSN	2374-7951
卷号	9 期号:5 页码:992-1007
DOI	10.1021/acscentsci.3c00063
摘要	Despite advances in characterizing the structures and functions of G protein-coupled receptors (GPCRs), our understanding of GPCR activation and signaling is still limited by the lack of information on conformational dynamics. It is particularly challenging to study the dynamics of GPCR complexes with their signaling partners because of their transient nature and low stability. Here, by combining cross-linking mass spectrometry (CLMS) with integrative structure modeling, we map the conformational ensemble of an activated GPCR-G protein complex at near-atomic resolution. The integrative structures describe heterogeneous conformations for a high number of potential alternative active states of the GLP-1 receptor-Gs complex. These structures show marked differences from the previously determined cryo-EM structure, especially at the receptor-Gs interface and in the interior of the Gs heterotrimer. Alanine-scanning mutagenesis coupled with pharmacological assays validates the functional significance of 24 interface residue contacts only observed in the integrative structures, yet absent in the cryo-EM structure. Through the integration of spatial connectivity data from CLMS with structure modeling, our study provides a new approach that is generalizable to characterizing the conformational dynamics of GPCR signaling complexes. © 2023 The Authors. Published by American Chemical Society.
关键词	Amino acids Dynamics Proteins Conformational dynamics Conformational ensemble Cross linking G protein G protein coupled receptors Integrative structure Receptor activation Receptor complex Receptor signaling Structure models
收录类别	EI
语种	英语
出版者	American Chemical Society
EI入藏号	20231914057265
EI主题词	Mass spectrometry
EI分类号	801 Chemistry ; 804.1 Organic Compounds
原始文献类型	Article in Press
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/301143
专题	iHuman研究所生命科学与技术学院 iHuman研究所_特聘教授组_Andrej Sali组 iHuman研究所_特聘教授组_Raymond Stevens组 iHuman研究所_PI研究组_水雯箐组生命科学与技术学院_硕士生生命科学与技术学院_博士生
通讯作者	Sun, Liping; Shui, Wenqing
作者单位	1.iHuman Institute, ShanghaiTech University, Shanghai; 201210, China; 2.School of Life Science and Technology, ShanghaiTech University, Shanghai; 201210, China; 3.University of Chinese Academy of Sciences, Beijing; 100049, China; 4.Structure Therapeutics, South San Francisco; CA; 94080, United States; 5.National Facility for Protein Science in Shanghai, Shanghai Advanced Research Institute, Chinese Academy of Science, Shanghai; 201210, China; 6.Biocreater (WuHan) Biotechnology Co., Ltd, Wuhan; 430075, China; 7.Beijing National Laboratory for Molecular Sciences, State Key Laboratory of Natural and Biomimetic Drugs, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, Department of Chemical Biology, College of Chemistry and Molecular Engineering, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing; 100871, China; 8.Quantitative Biosciences Institute, University of California, San Francisco, San Francisco; CA; 94143, United States; 9.Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco; CA; 94143, United States; 10.Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco; CA; 94143, United States
第一作者单位	iHuman研究所; 生命科学与技术学院
通讯作者单位	iHuman研究所; 生命科学与技术学院
第一作者的第一单位	iHuman研究所
推荐引用方式 GB/T 7714	Yuan, Shijia,Xia, Lisha,Wang, Chenxi,et al. Conformational Dynamics of the Activated GLP-1 Receptor-Gs Complex Revealed by Cross-Linking Mass Spectrometry and Integrative Structure Modeling[J]. ACS CENTRAL SCIENCE,2023,9(5):992-1007.
APA	Yuan, Shijia.,Xia, Lisha.,Wang, Chenxi.,Wu, Fan.,Zhang, Bingjie.,...&Shui, Wenqing.(2023).Conformational Dynamics of the Activated GLP-1 Receptor-Gs Complex Revealed by Cross-Linking Mass Spectrometry and Integrative Structure Modeling.ACS CENTRAL SCIENCE,9(5),992-1007.
MLA	Yuan, Shijia,et al."Conformational Dynamics of the Activated GLP-1 Receptor-Gs Complex Revealed by Cross-Linking Mass Spectrometry and Integrative Structure Modeling".ACS CENTRAL SCIENCE 9.5(2023):992-1007.