Distinct structure and gating mechanism in diverse NMDA receptors with GluN2C and GluN2D subunits
文献类型：期刊论文
| 作者 | Zhang, Jilin4,5; Zhang, Ming3,4; Wang, Qinrui2; Wen, Han2; Liu, Zheyi1; Wang, Fangjun1; Wang, Yuhang2; Yao, Fenyong5; Song, Nan5; Kou, Zengwei5 |
| 刊名 | NATURE STRUCTURAL & MOLECULAR BIOLOGY
 |
| 出版日期 | 2023-05-01 |
| 卷号 | 30期号:5页码:629-+ |
| DOI | 10.1038/s41594-023-00959-z |
| 文献子类 | Article |
| 英文摘要 | Zhang et al. describe structures, diverse function and subunit-specific pharmacology of three major GluN2C- and GluN2D-incorporated NMDA receptors known to exist in the brain. N-methyl-d-aspartate (NMDA) receptors are heterotetramers comprising two GluN1 and two alternate GluN2 (N2A-N2D) subunits. Here we report full-length cryo-EM structures of the human N1-N2D di-heterotetramer (di-receptor), rat N1-N2C di-receptor and N1-N2A-N2C tri-heterotetramer (tri-receptor) at a best resolution of 3.0 angstrom. The bilobate N-terminal domain (NTD) in N2D intrinsically adopts a closed conformation, leading to a compact NTD tetramer in the N1-N2D receptor. Additionally, crosslinking the ligand-binding domain (LBD) of two N1 protomers significantly elevated the channel open probability (Po) in N1-N2D di-receptors. Surprisingly, the N1-N2C di-receptor adopted both symmetric (minor) and asymmetric (major) conformations, the latter further locked by an allosteric potentiator, PYD-106, binding to a pocket between the NTD and LBD in only one N2C protomer. Finally, the N2A and N2C subunits in the N1-N2A-N2C tri-receptor display a conformation close to one protomer in the N1-N2A and N1-N2C di-receptors, respectively. These findings provide a comprehensive structural understanding of diverse function in major NMDA receptor subtypes. |
| WOS关键词 | CRYO-EM ; ALLOSTERIC MODULATORS ; MODEL ; INHIBITION ; DYNAMICS ; NEUROTRANSMISSION ; TRANSITIONS ; SIMULATIONS ; ACTIVATION ; EXPRESSION |
| WOS研究方向 | Biochemistry & Molecular Biology ; Biophysics ; Cell Biology |
| 语种 | 英语 |
| WOS记录号 | WOS:000955565600002 |
| 出版者 | NATURE PORTFOLIO |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/309664]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Zhu, Shujia |
| 作者单位 | 1.Chinese Acad Sci, Dalian Inst Chem Phys, CAS Key Lab Separat Sci Analyt Chem, Dalian, Peoples R China 2.DP Technol, Beijing, Peoples R China; 3.Chinese Acad Sci, Shanghai Inst Mat Med, Ctr Neurol & Psychiat Res & Drug Discovery, State Key Lab Drug Res, Shanghai, Peoples R China; 4.Univ Chinese Acad Sci, Beijing, Peoples R China; 5.Chinese Acad Sci, Inst Neurosci, CAS Ctr Excellence Brain Sci & Intelligence Techno, State Key Lab Neurosci, Shanghai, Peoples R China; |
| 推荐引用方式 GB/T 7714 | Zhang, Jilin,Zhang, Ming,Wang, Qinrui,et al. Distinct structure and gating mechanism in diverse NMDA receptors with GluN2C and GluN2D subunits[J]. NATURE STRUCTURAL & MOLECULAR BIOLOGY,2023,30(5):629-+. |
| APA | Zhang, Jilin.,Zhang, Ming.,Wang, Qinrui.,Wen, Han.,Liu, Zheyi.,...&Zhu, Shujia.(2023).Distinct structure and gating mechanism in diverse NMDA receptors with GluN2C and GluN2D subunits.NATURE STRUCTURAL & MOLECULAR BIOLOGY,30(5),629-+. |
| MLA | Zhang, Jilin,et al."Distinct structure and gating mechanism in diverse NMDA receptors with GluN2C and GluN2D subunits".NATURE STRUCTURAL & MOLECULAR BIOLOGY 30.5(2023):629-+. |
入库方式： OAI收割
来源：上海药物研究所
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