Structural Basis of the Proton Sensitivity of Human GluN1-GluN2A NMDA Receptors
Summary: 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...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2018-12-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124718318473 |
| _version_ | 1818939591045939200 |
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| author | Jin-Bao Zhang Shenghai Chang Pan Xu Miao Miao Hangjun Wu Youyi Zhang Tongtong Zhang Han Wang Jilin Zhang Chun Xie Nan Song Cheng Luo Xing Zhang Shujia Zhu |
| author_facet | Jin-Bao Zhang Shenghai Chang Pan Xu Miao Miao Hangjun Wu Youyi Zhang Tongtong Zhang Han Wang Jilin Zhang Chun Xie Nan Song Cheng Luo Xing Zhang Shujia Zhu |
| author_sort | Jin-Bao Zhang |
| collection | DOAJ |
| description | Summary: 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. : NMDA receptor activity is bi-directionally modulated by glutamate and protons co-released from presynaptic vesicles. Combining cryo-EM and molecular dynamics simulation, Zhang et al. demonstrate the structure and subunit arrangement of the human GluN1-GluN2A NMDA receptor in the agonist-bound state, revealing how protons alter the conformation of the entire tetrameric complex. Keywords: ionotropic glutamate receptor, human GluN1-GluN2A NMDA receptor, cryo-electron microscopy, N-terminal domain, proton sensor, molecular dynamics simulation |
| first_indexed | 2024-12-20T06:26:11Z |
| format | Article |
| id | doaj.art-a565a9a6302a48e2aa920e3aff00d2fb |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-20T06:26:11Z |
| publishDate | 2018-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-a565a9a6302a48e2aa920e3aff00d2fb2022-12-21T19:50:17ZengElsevierCell Reports2211-12472018-12-01251335823590.e4Structural Basis of the Proton Sensitivity of Human GluN1-GluN2A NMDA ReceptorsJin-Bao Zhang0Shenghai Chang1Pan Xu2Miao Miao3Hangjun Wu4Youyi Zhang5Tongtong Zhang6Han Wang7Jilin Zhang8Chun Xie9Nan Song10Cheng Luo11Xing Zhang12Shujia Zhu13Institute of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, ChinaDepartment of Biophysics, and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China; Center of Cryo Electron Microscopy, Zhejiang University School of Medicine, Hangzhou, ChinaDrug 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; University of Chinese Academy of Sciences, Beijing, ChinaDepartment of Biophysics, and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, ChinaCenter of Cryo Electron Microscopy, Zhejiang University School of Medicine, Hangzhou, ChinaInstitute of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China; University of Chinese Academy of Sciences, Beijing, ChinaInstitute of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China; University of Chinese Academy of Sciences, Beijing, ChinaInstitute of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China; University of Chinese Academy of Sciences, Beijing, ChinaInstitute of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, ChinaInstitute of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, ChinaInstitute of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, ChinaDrug 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; University of Chinese Academy of Sciences, Beijing, China; Corresponding authorDepartment of Biophysics, and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China; Center of Cryo Electron Microscopy, Zhejiang University School of Medicine, Hangzhou, China; Corresponding authorInstitute of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China; University of Chinese Academy of Sciences, Beijing, China; Corresponding authorSummary: 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. : NMDA receptor activity is bi-directionally modulated by glutamate and protons co-released from presynaptic vesicles. Combining cryo-EM and molecular dynamics simulation, Zhang et al. demonstrate the structure and subunit arrangement of the human GluN1-GluN2A NMDA receptor in the agonist-bound state, revealing how protons alter the conformation of the entire tetrameric complex. Keywords: ionotropic glutamate receptor, human GluN1-GluN2A NMDA receptor, cryo-electron microscopy, N-terminal domain, proton sensor, molecular dynamics simulationhttp://www.sciencedirect.com/science/article/pii/S2211124718318473 |
| spellingShingle | Jin-Bao Zhang Shenghai Chang Pan Xu Miao Miao Hangjun Wu Youyi Zhang Tongtong Zhang Han Wang Jilin Zhang Chun Xie Nan Song Cheng Luo Xing Zhang Shujia Zhu Structural Basis of the Proton Sensitivity of Human GluN1-GluN2A NMDA Receptors Cell Reports |
| title | Structural Basis of the Proton Sensitivity of Human GluN1-GluN2A NMDA Receptors |
| title_full | Structural Basis of the Proton Sensitivity of Human GluN1-GluN2A NMDA Receptors |
| title_fullStr | Structural Basis of the Proton Sensitivity of Human GluN1-GluN2A NMDA Receptors |
| title_full_unstemmed | Structural Basis of the Proton Sensitivity of Human GluN1-GluN2A NMDA Receptors |
| title_short | Structural Basis of the Proton Sensitivity of Human GluN1-GluN2A NMDA Receptors |
| title_sort | structural basis of the proton sensitivity of human glun1 glun2a nmda receptors |
| url | http://www.sciencedirect.com/science/article/pii/S2211124718318473 |
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