Structural insights into dimerization and activation of the mGlu2-mGlu3 and mGlu2-mGlu4 heterodimers
文献类型：期刊论文
| 作者 | Wang, Xinwei1,2; Wang, Mu1,3; Xu, Tuo1,2; Feng, Ye1,3; Shao, Qiang1,2 ; Han, Shuo1,2,4; Chu, Xiaojing1; Xu, Yechun1,2,4; Lin, Shuling1; Zhao, Qiang1,2,5
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| 刊名 | CELL RESEARCH
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| 出版日期 | 2023-06-08 |
| 页码 | 13 |
| ISSN号 | 1001-0602 |
| DOI | 10.1038/s41422-023-00830-2 |
| 通讯作者 | Lin, Shuling(linshuling@simm.ac.cn) ; Zhao, Qiang(zhaoq@simm.ac.cn) ; Wu, Beili(beiliwu@simm.ac.cn) |
| 英文摘要 | Heterodimerization of the metabotropic glutamate receptors (mGlus) has shown importance in the functional modulation of the receptors and offers potential drug targets for treating central nervous system diseases. However, due to a lack of molecular details of the mGlu heterodimers, understanding of the mechanisms underlying mGlu heterodimerization and activation is limited. Here we report twelve cryo-electron microscopy (cryo-EM) structures of the mGlu2-mGlu3 and mGlu2-mGlu4 heterodimers in different conformational states, including inactive, intermediate inactive, intermediate active and fully active conformations. These structures provide a full picture of conformational rearrangement of mGlu2-mGlu3 upon activation. The Venus flytrap domains undergo a sequential conformational change, while the transmembrane domains exhibit a substantial rearrangement from an inactive, symmetric dimer with diverse dimerization patterns to an active, asymmetric dimer in a conserved dimerization mode. Combined with functional data, these structures reveal that stability of the inactive conformations of the subunits and the subunit-G protein interaction pattern are determinants of asymmetric signal transduction of the heterodimers. Furthermore, a novel binding site for two mGlu4 positive allosteric modulators was observed in the asymmetric dimer interfaces of the mGlu2-mGlu4 heterodimer and mGlu4 homodimer, and may serve as a drug recognition site. These findings greatly extend our knowledge about signal transduction of the mGlus. |
| WOS关键词 | METABOTROPIC GLUTAMATE RECEPTORS ; POSITIVE ALLOSTERIC MODULATOR ; MOLECULAR-DYNAMICS ; RODENT MODELS ; GROUP-II ; PHARMACOLOGY ; ANTAGONIST ; ACCURACY ; CHLORIDE ; POTENT |
| 资助项目 | National Key R&D Program of China[2022YFA1302900] ; National Natural~Science Foundation of China[31825010] ; National Natural~Science Foundation of China[82121005] ; CAS Strategic Priority Research Program[XDB37030100] ; Shanghai Science and Technology Committee grant[JCYJ-SHFY-2021008] ; Shanghai Pilot Program for Basic Research - Chinese Academy of Sciences, Shanghai Branch ; [23YF1456600] |
| WOS研究方向 | Cell Biology |
| 语种 | 英语 |
| WOS记录号 | WOS:001002888800001 |
| 出版者 | SPRINGERNATURE |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/306665]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Lin, Shuling; Zhao, Qiang; Wu, Beili |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai, Peoples R China 2.Univ Chinese Acad Sci, Beijing, Peoples R China 3.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China 4.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou, Zhejiang, Peoples R China 5.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan, Guangdong, Peoples R China |
| 推荐引用方式 GB/T 7714 | Wang, Xinwei,Wang, Mu,Xu, Tuo,et al. Structural insights into dimerization and activation of the mGlu2-mGlu3 and mGlu2-mGlu4 heterodimers[J]. CELL RESEARCH,2023:13. |
| APA | Wang, Xinwei.,Wang, Mu.,Xu, Tuo.,Feng, Ye.,Shao, Qiang.,...&Wu, Beili.(2023).Structural insights into dimerization and activation of the mGlu2-mGlu3 and mGlu2-mGlu4 heterodimers.CELL RESEARCH,13. |
| MLA | Wang, Xinwei,et al."Structural insights into dimerization and activation of the mGlu2-mGlu3 and mGlu2-mGlu4 heterodimers".CELL RESEARCH (2023):13. |
入库方式： OAI收割
来源：上海药物研究所
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