Structural Basis of the Proton Sensitivity of Human GluN1-GluN2A NMDA Receptors
文献类型：期刊论文
| 作者 | Zhang, Jin-Bao5; Chang, Shenghai1,3; Xu, Pan2,4; Miao, Miao3; Wu, Hangjun1; Zhang, Youyi4,5; Zhang, Tongtong4,5; Wang, Han4,5; Zhang, Jilin5; Xie, Chun5 |
| 刊名 | Cell reports
 |
| 出版日期 | 2018-12-26 |
| 卷号 | 25期号:13页码:3582-3590.e4 |
| ISSN号 | 2211-1247 |
| DOI | 10.1016/j.celrep.2018.11.071 |
| 文献子类 | Article |
| 英文摘要 | N-methyl-D-aspartate (NMDA) receptors are critical for synaptic development and plasticity. While glutamate is the primary agonist, protons can modulate NMDA receptor activity at synapses during vesicle exocytosis by mechanisms that are unknown. We used cryo-electron microscopy to solve the structures of the human GluN1-GluN2A NMDA receptor at pH 7.8 and pH 6.3. Our structures demonstrate that the proton sensor predominantly resides in the N-terminal domain (NTD) of the GluN2A subunit and reveal the allosteric coupling mechanism between the proton sensor and the channel gate. Under high-pH conditions, the GluN2A-NTD adopts an "open-and-twisted" conformation. However, upon protonation at the lower pH, the GluN2A-NTD transits from an open- to closed-cleft conformation, causing rearrangements between the tetrameric NTDs and agonist-binding domains. The conformational mobility observed in our structures (presumably from protonation) is supported by molecular dynamics simulation. Our findings reveal the structural mechanisms by which protons allosterically inhibit human GluN1-GluN2A receptor activity. |
| 语种 | 英语 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/266247]  |
| 专题 | 药物发现与设计中心 |
| 通讯作者 | Luo, Cheng; Zhang, Xing; Zhu, Shujia |
| 作者单位 | 1.Center of Cryo Electron Microscopy, Zhejiang University School of Medicine, Hangzhou, China; 2.Drug Discovery and Design Center, State Key Laboratory of Drug Research, CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; 3.Department of Biophysics, and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China; 4.University of Chinese Academy of Sciences, Beijing, China; 5.Institute of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China; 6.University of Chinese Academy of Sciences, Beijing, China |
| 推荐引用方式 GB/T 7714 | Zhang, Jin-Bao,Chang, Shenghai,Xu, Pan,et al. Structural Basis of the Proton Sensitivity of Human GluN1-GluN2A NMDA Receptors[J]. Cell reports,2018,25(13):3582-3590.e4. |
| APA | Zhang, Jin-Bao.,Chang, Shenghai.,Xu, Pan.,Miao, Miao.,Wu, Hangjun.,...&Zhu, Shujia.(2018).Structural Basis of the Proton Sensitivity of Human GluN1-GluN2A NMDA Receptors.Cell reports,25(13),3582-3590.e4. |
| MLA | Zhang, Jin-Bao,et al."Structural Basis of the Proton Sensitivity of Human GluN1-GluN2A NMDA Receptors".Cell reports 25.13(2018):3582-3590.e4. |
入库方式： OAI收割
来源：上海药物研究所
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