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- PDB-7eu7: Structure of the human GluN1-GluN2A NMDA receptor in complex with... -
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Basic information
Entry | Database: PDB / ID: 7eu7 | ||||||||||||||||||||||||||||||
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Title | Structure of the human GluN1-GluN2A NMDA receptor in complex with S-ketamine, glycine and glutamate | ||||||||||||||||||||||||||||||
![]() | (Glutamate receptor ionotropic, NMDA ...) x 2 | ||||||||||||||||||||||||||||||
![]() | MEMBRANE PROTEIN / NMDA receptor / ketamine / enantiomer / rapid antidepressant / cryo-EM structure | ||||||||||||||||||||||||||||||
Function / homology | ![]() excitatory chemical synaptic transmission / directional locomotion / Synaptic adhesion-like molecules / serotonin metabolic process / protein localization to postsynaptic membrane / propylene metabolic process / response to glycine / sleep / activation of cysteine-type endopeptidase activity / regulation of monoatomic cation transmembrane transport ...excitatory chemical synaptic transmission / directional locomotion / Synaptic adhesion-like molecules / serotonin metabolic process / protein localization to postsynaptic membrane / propylene metabolic process / response to glycine / sleep / activation of cysteine-type endopeptidase activity / regulation of monoatomic cation transmembrane transport / Assembly and cell surface presentation of NMDA receptors / glutamate receptor signaling pathway / NMDA glutamate receptor activity / Neurexins and neuroligins / NMDA selective glutamate receptor complex / calcium ion transmembrane import into cytosol / glutamate binding / positive regulation of reactive oxygen species biosynthetic process / protein heterotetramerization / glycine binding / positive regulation of calcium ion transport into cytosol / dopamine metabolic process / Negative regulation of NMDA receptor-mediated neuronal transmission / Unblocking of NMDA receptors, glutamate binding and activation / startle response / regulation of neuronal synaptic plasticity / monoatomic cation transmembrane transport / monoatomic cation transport / positive regulation of excitatory postsynaptic potential / Long-term potentiation / ligand-gated monoatomic ion channel activity / excitatory synapse / calcium ion homeostasis / synaptic cleft / MECP2 regulates neuronal receptors and channels / glutamate-gated calcium ion channel activity / sensory perception of pain / EPHB-mediated forward signaling / response to amphetamine / Ras activation upon Ca2+ influx through NMDA receptor / ionotropic glutamate receptor signaling pathway / neurogenesis / positive regulation of synaptic transmission, glutamatergic / regulation of membrane potential / excitatory postsynaptic potential / transmitter-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential / synaptic membrane / synaptic transmission, glutamatergic / long-term synaptic potentiation / postsynaptic density membrane / visual learning / cytoplasmic vesicle membrane / protein catabolic process / brain development / regulation of synaptic plasticity / negative regulation of protein catabolic process / terminal bouton / memory / response to wounding / synaptic vesicle / signaling receptor activity / presynaptic membrane / amyloid-beta binding / RAF/MAP kinase cascade / chemical synaptic transmission / postsynaptic membrane / response to ethanol / dendritic spine / postsynaptic density / learning or memory / calmodulin binding / neuron projection / response to xenobiotic stimulus / positive regulation of apoptotic process / glutamatergic synapse / synapse / dendrite / calcium ion binding / endoplasmic reticulum membrane / protein-containing complex binding / cell surface / positive regulation of transcription by RNA polymerase II / zinc ion binding / plasma membrane / cytoplasm Similarity search - Function | ||||||||||||||||||||||||||||||
Biological species | ![]() | ||||||||||||||||||||||||||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.5 Å | ||||||||||||||||||||||||||||||
![]() | Zhang, Y. / Zhang, T. / Zhu, S. | ||||||||||||||||||||||||||||||
Funding support | ![]()
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![]() | ![]() 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
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Structure viewer | Molecule: ![]() ![]() |
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PDBx/mmCIF format | ![]() | 511.3 KB | Display | ![]() |
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PDB format | ![]() | 405.7 KB | Display | ![]() |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
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-Validation report
Arichive directory | ![]() ![]() | HTTPS FTP |
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-Related structure data
Related structure data | ![]() 31308MC ![]() 7eu8C M: map data used to model this data C: citing same article ( |
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Similar structure data |
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Links
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Assembly
Deposited unit | ![]()
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Components
-Glutamate receptor ionotropic, NMDA ... , 2 types, 4 molecules ACBD
#1: Protein | Mass: 95236.078 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() #2: Protein | Mass: 94136.016 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() |
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-Sugars , 1 types, 24 molecules ![](data/chem/img/NAG.gif)
#3: Sugar | ChemComp-NAG / |
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-Non-polymers , 3 types, 5 molecules ![](data/chem/img/GLY.gif)
![](data/chem/img/GLU.gif)
![](data/chem/img/JC9.gif)
![](data/chem/img/GLU.gif)
![](data/chem/img/JC9.gif)
#4: Chemical | #5: Chemical | #6: Chemical | ChemComp-JC9 / ( | |
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-Details
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 |
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Sample preparation
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Source (recombinant) |
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Buffer solution | pH: 8 | ||||||||||||||||||||||||
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES | ||||||||||||||||||||||||
Vitrification | Cryogen name: ETHANE |
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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: ![]() |
Electron lens | Mode: BRIGHT FIELD |
Image recording | Electron dose: 60 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) |
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Processing
CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION |
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3D reconstruction | Resolution: 3.5 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 265055 / Symmetry type: POINT |