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Yorodumi- PDB-7eu8: Structure of the human GluN1-GluN2B NMDA receptor in complex with... -
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-Basic information
Entry | Database: PDB / ID: 7eu8 | ||||||||||||||||||||||||||||||
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Title | Structure of the human GluN1-GluN2B NMDA receptor in complex with S-ketamine,glycine and glutamate | ||||||||||||||||||||||||||||||
Components |
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Keywords | MEMBRANE PROTEIN / NMDA receptor / ketamine / enantiomer / rapid antidepressant / cryo-EM structure | ||||||||||||||||||||||||||||||
Function / homology | Function and homology information excitatory chemical synaptic transmission / Activated NTRK2 signals through FYN / Synaptic adhesion-like molecules / propylene metabolic process / response to glycine / positive regulation of cysteine-type endopeptidase activity / negative regulation of dendritic spine maintenance / regulation of monoatomic cation transmembrane transport / glutamate receptor signaling pathway / Assembly and cell surface presentation of NMDA receptors ...excitatory chemical synaptic transmission / Activated NTRK2 signals through FYN / Synaptic adhesion-like molecules / propylene metabolic process / response to glycine / positive regulation of cysteine-type endopeptidase activity / negative regulation of dendritic spine maintenance / regulation of monoatomic cation transmembrane transport / glutamate receptor signaling pathway / Assembly and cell surface presentation of NMDA receptors / NMDA glutamate receptor activity / Neurexins and neuroligins / NMDA selective glutamate receptor complex / glutamate-gated calcium ion channel activity / calcium ion transmembrane import into cytosol / protein heterotetramerization / glutamate binding / positive regulation of reactive oxygen species biosynthetic process / glycine binding / positive regulation of calcium ion transport into cytosol / Negative regulation of NMDA receptor-mediated neuronal transmission / Unblocking of NMDA receptors, glutamate binding and activation / monoatomic cation transmembrane transport / monoatomic cation transport / regulation of neuronal synaptic plasticity / positive regulation of excitatory postsynaptic potential / ligand-gated monoatomic ion channel activity / Long-term potentiation / excitatory synapse / calcium ion homeostasis / synaptic cleft / MECP2 regulates neuronal receptors and channels / ligand-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential / EPHB-mediated forward signaling / ionotropic glutamate receptor signaling pathway / Ras activation upon Ca2+ influx through NMDA receptor / excitatory postsynaptic potential / positive regulation of synaptic transmission, glutamatergic / synaptic membrane / synaptic transmission, glutamatergic / transmitter-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential / regulation of membrane potential / long-term synaptic potentiation / postsynaptic density membrane / visual learning / regulation of synaptic plasticity / brain development / terminal bouton / late endosome / synaptic vesicle / signaling receptor activity / amyloid-beta binding / RAF/MAP kinase cascade / chemical synaptic transmission / postsynaptic membrane / response to ethanol / dendritic spine / postsynaptic density / learning or memory / lysosome / cytoskeleton / calmodulin binding / neuron projection / synapse / calcium ion binding / dendrite / protein-containing complex binding / endoplasmic reticulum membrane / cell surface / positive regulation of transcription by RNA polymerase II / zinc ion binding / plasma membrane / cytoplasm Similarity search - Function | ||||||||||||||||||||||||||||||
Biological species | Homo sapiens (human) | ||||||||||||||||||||||||||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4.07 Å | ||||||||||||||||||||||||||||||
Authors | Zhang, T. / Zhang, Y. / Zhu, S. | ||||||||||||||||||||||||||||||
Funding support | China, 9items
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Citation | Journal: Nature / Year: 2021 Title: Structural basis of ketamine action on human NMDA receptors. Authors: Youyi Zhang / Fei Ye / Tongtong Zhang / Shiyun Lv / Liping Zhou / Daohai Du / He Lin / Fei Guo / Cheng Luo / Shujia Zhu / Abstract: Ketamine is a non-competitive channel blocker of N-methyl-D-aspartate (NMDA) receptors. A single sub-anaesthetic dose of ketamine produces rapid (within hours) and long-lasting antidepressant effects ...Ketamine is a non-competitive channel blocker of N-methyl-D-aspartate (NMDA) receptors. A single sub-anaesthetic dose of ketamine produces rapid (within hours) and long-lasting antidepressant effects in patients who are resistant to other antidepressants. Ketamine is a racemic mixture of S- and R-ketamine enantiomers, with S-ketamine isomer being the more active antidepressant. Here we describe the cryo-electron microscope structures of human GluN1-GluN2A and GluN1-GluN2B NMDA receptors in complex with S-ketamine, glycine and glutamate. Both electron density maps uncovered the binding pocket for S-ketamine in the central vestibule between the channel gate and selectivity filter. Molecular dynamics simulation showed that S-ketamine moves between two distinct locations within the binding pocket. Two amino acids-leucine 642 on GluN2A (homologous to leucine 643 on GluN2B) and asparagine 616 on GluN1-were identified as key residues that form hydrophobic and hydrogen-bond interactions with ketamine, and mutations at these residues reduced the potency of ketamine in blocking NMDA receptor channel activity. These findings show structurally how ketamine binds to and acts on human NMDA receptors, and pave the way for the future development of ketamine-based antidepressants. | ||||||||||||||||||||||||||||||
History |
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-Structure visualization
Movie |
Movie viewer |
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Structure viewer | Molecule: MolmilJmol/JSmol |
-Downloads & links
-Download
PDBx/mmCIF format | 7eu8.cif.gz | 464.9 KB | Display | PDBx/mmCIF format |
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PDB format | pdb7eu8.ent.gz | 352.7 KB | Display | PDB format |
PDBx/mmJSON format | 7eu8.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 7eu8_validation.pdf.gz | 843.1 KB | Display | wwPDB validaton report |
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Full document | 7eu8_full_validation.pdf.gz | 853.1 KB | Display | |
Data in XML | 7eu8_validation.xml.gz | 70.6 KB | Display | |
Data in CIF | 7eu8_validation.cif.gz | 110.4 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/eu/7eu8 ftp://data.pdbj.org/pub/pdb/validation_reports/eu/7eu8 | HTTPS FTP |
-Related structure data
Related structure data | 31309MC 7eu7C M: map data used to model this data C: citing same article (ref.) |
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Similar structure data |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
#1: Protein | Mass: 95236.078 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: GRIN1, NMDAR1 / Cell line (production host): HEK293F / Production host: Homo sapiens (human) / References: UniProt: Q05586 #2: Protein | Mass: 96575.508 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: GRIN2B / Production host: Homo sapiens (human) / References: UniProt: Q13224 #3: Sugar | ChemComp-NAG / #4: Chemical | ChemComp-JC9 / ( | Has ligand of interest | Y | |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-Sample preparation
Component | Name: tetrameric complex of GluN1 and GluN2B subunits / Type: COMPLEX / Entity ID: #1-#2 / Source: RECOMBINANT |
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Molecular weight | Value: 383.22 kDa/nm / Experimental value: NO |
Source (natural) | Organism: Homo sapiens (human) |
Source (recombinant) | Organism: Homo sapiens (human) |
Buffer solution | pH: 8 |
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Vitrification | Cryogen name: ETHANE |
-Electron microscopy imaging
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: OTHER |
Electron lens | Mode: BRIGHT FIELD |
Image recording | Electron dose: 60 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) |
-Processing
CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION |
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3D reconstruction | Resolution: 4.07 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 159306 / Symmetry type: POINT |
Atomic model building | Protocol: RIGID BODY FIT / Space: REAL |