Targeted Proteomics Combined with Affinity Mass Spectrometry Analysis Reveals Antagonist E7 Acts As an Intracellular Covalent Ligand of Orphan Receptor GPR52
文献类型：期刊论文
| 作者 | Ma, Mengna5,6; Guo, Shimeng1; Lin, Xi5; Li, Shanshan5; Wu, Yiran5; Zeng, Yanping2; Hu, Youhong2,4 ; Zhao, Suwen5; Xu, Fei5; Xie, Xin1,3,4
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| 刊名 | ACS CHEMICAL BIOLOGY
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| 出版日期 | 2020-12-18 |
| 卷号 | 15期号:12页码:3275-3284 |
| ISSN号 | 1554-8929 |
| DOI | 10.1021/acschembio.0c00867 |
| 通讯作者 | Shui, Wenqing(shuiwq@shanghaitech.edu.cn) |
| 英文摘要 | The GPR52, a class A orphan G protein-coupled receptor (GPCR), is regarded as a promising therapeutic target for the treatment of Huntington's disease and multiple psychiatric disorders. Although the recently solved structure of GPR52 has revealed a binding mechanism likely shared by all reported agonists, the small molecule antagonist E7 cannot fit into this agonist-binding pocket, and its interaction mode with the receptor remains unknown. Here, we employed targeted proteomics and affinity mass spectrometry approaches to uncover a unique binding mode of E7 which acts as a covalent and allosteric ligand of GPR52. Among three Cys residues identified in this study to form covalent conjugates with E7, the intracellular C1564.40 makes the most significant contribution to the antagonism activity of E7. Discovery of this novel intracellular site for covalent attachment of an antagonist would facilitate the design of GPR52-selective negative allosteric modulators which could serve as potential therapeutics for treating Huntington's disease. |
| WOS关键词 | PROTEIN ; IDENTIFICATION ; ACTIVATION ; AGONIST |
| 资助项目 | National Key Research and Development Program of China[2018YFA0507000] ; National Natural Science Foundation of China[31971362] ; National Natural Science Foundation of China[81730099] ; National Natural Science Foundation of China[81861128023] ; National Science and Technology Major Projects for New Drug Development[2018ZX0971100-2-002-013] ; ShanghaiTech University |
| WOS研究方向 | Biochemistry & Molecular Biology |
| 语种 | 英语 |
| WOS记录号 | WOS:000608852300023 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/296153]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Shui, Wenqing |
| 作者单位 | 1.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210046, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China 3.Shanghai Inst Mat Med, Natl Ctr Drug Screening, CAS Lab Receptor Res, Shanghai 201203, Peoples R China 4.Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China 5.ShanghaiTech Univ, Sch Life Sci & Technol, iHuman Inst, Shanghai 201210, Peoples R China 6.Univ Chinese Acad Sci, Beijing 100049, Peoples R China |
| 推荐引用方式 GB/T 7714 | Ma, Mengna,Guo, Shimeng,Lin, Xi,et al. Targeted Proteomics Combined with Affinity Mass Spectrometry Analysis Reveals Antagonist E7 Acts As an Intracellular Covalent Ligand of Orphan Receptor GPR52[J]. ACS CHEMICAL BIOLOGY,2020,15(12):3275-3284. |
| APA | Ma, Mengna.,Guo, Shimeng.,Lin, Xi.,Li, Shanshan.,Wu, Yiran.,...&Shui, Wenqing.(2020).Targeted Proteomics Combined with Affinity Mass Spectrometry Analysis Reveals Antagonist E7 Acts As an Intracellular Covalent Ligand of Orphan Receptor GPR52.ACS CHEMICAL BIOLOGY,15(12),3275-3284. |
| MLA | Ma, Mengna,et al."Targeted Proteomics Combined with Affinity Mass Spectrometry Analysis Reveals Antagonist E7 Acts As an Intracellular Covalent Ligand of Orphan Receptor GPR52".ACS CHEMICAL BIOLOGY 15.12(2020):3275-3284. |
入库方式： OAI收割
来源：上海药物研究所
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