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- EMDB-9716: Structure of the human GluN1/GluN2A NMDA receptor in the glutamat... -

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Basic information

Entry
Database: EMDB / ID: EMD-9716
TitleStructure of the human GluN1/GluN2A NMDA receptor in the glutamate/glycine-bound state at pH 6.3, Class II
Map data
SampleHuman GluN1/GluN2A NMDA receptors in the glutamate/glycine bound state at pH 6.3, Class II
  • (Glutamate receptor ionotropic, NMDA ...) x 2
Function / homology
Function and homology information


excitatory chemical synaptic transmission / directional locomotion / pons maturation / response to glycine / propylene metabolic process / glutamate receptor signaling pathway / protein localization to postsynaptic membrane / serotonin metabolic process / conditioned taste aversion / olfactory learning ...excitatory chemical synaptic transmission / directional locomotion / pons maturation / response to glycine / propylene metabolic process / glutamate receptor signaling pathway / protein localization to postsynaptic membrane / serotonin metabolic process / conditioned taste aversion / olfactory learning / regulation of respiratory gaseous exchange / neurotransmitter binding / glutamate-gated calcium ion channel activity / calcium ion transmembrane import into cytosol / activation of cysteine-type endopeptidase activity / regulation of synapse assembly / NMDA glutamate receptor activity / sleep / NMDA selective glutamate receptor complex / glutamate binding / startle response / glycine binding / neurogenesis / positive regulation of cysteine-type endopeptidase activity / positive regulation of reactive oxygen species biosynthetic process / cation transport / calcium ion homeostasis / dopamine metabolic process / regulation of dendrite morphogenesis / positive regulation of calcium ion transport into cytosol / suckling behavior / male mating behavior / regulation of axonogenesis / excitatory synapse / social behavior / response to morphine / long-term memory / response to amphetamine / regulation of NMDA receptor activity / positive regulation of excitatory postsynaptic potential / synaptic cleft / excitatory postsynaptic potential / integral component of postsynaptic density membrane / long-term synaptic potentiation / prepulse inhibition / synaptic membrane / glutamate receptor activity / transmitter-gated ion channel activity involved in regulation of postsynaptic membrane potential / ionotropic glutamate receptor signaling pathway / adult locomotory behavior / sensory perception of pain / visual learning / synaptic transmission, glutamatergic / regulation of membrane potential / regulation of synaptic plasticity / postsynaptic density membrane / protein heterotetramerization / cerebral cortex development / regulation of long-term neuronal synaptic plasticity / memory / presynaptic membrane / terminal bouton / ephrin receptor signaling pathway / cytoplasmic vesicle membrane / negative regulation of protein catabolic process / response to wounding / modulation of chemical synaptic transmission / postsynaptic membrane / brain development / chemical synaptic transmission / synaptic vesicle / amyloid-beta binding / calmodulin binding / negative regulation of neuron apoptotic process / response to ethanol / learning or memory / dendritic spine / postsynaptic density / MAPK cascade / neuron projection / synapse / protein-containing complex binding / cell junction / positive regulation of apoptotic process / glutamatergic synapse / signaling receptor binding / dendrite / calcium ion binding / endoplasmic reticulum / integral component of plasma membrane / cell surface / positive regulation of transcription by RNA polymerase II / cell / zinc ion binding / plasma membrane / cytoplasm
Glutamate [NMDA] receptor, epsilon subunit, C-terminal / Calmodulin-binding domain C0, NMDA receptor, NR1 subunit / Ionotropic glutamate receptor / Ionotropic glutamate receptor, metazoa / Periplasmic binding protein-like I / Ionotropic glutamate receptor, L-glutamate and glycine-binding domain / Receptor, ligand binding region
Glutamate receptor ionotropic, NMDA 1 / Glutamate receptor ionotropic, NMDA 2A
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 5.5 Å
AuthorsZhang J / Chang S / Zhang X / Zhu S
CitationJournal: Cell Rep / Year: 2018
Title: Structural Basis of the Proton Sensitivity of Human GluN1-GluN2A NMDA Receptors.
Authors: 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 /
Abstract: 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 ...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.
Validation ReportPDB-ID: 6irg

SummaryFull reportAbout validation report
History
DepositionNov 12, 2018-
Header (metadata) releaseJan 16, 2019-
Map releaseJan 16, 2019-
UpdateJun 5, 2019-
Current statusJun 5, 2019Processing site: PDBj / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 2.58
  • Imaged by UCSF Chimera
  • Download
  • Surface view colored by cylindrical radius
  • Surface level: 2.58
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: : PDB-6irg
  • Surface level: 2.58
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

Downloads & links

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Map

FileDownload / File: emd_9716.map.gz / Format: CCP4 / Size: 52.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.01 Å/pix.
x 240 pix.
= 242.4 Å
1.01 Å/pix.
x 240 pix.
= 242.4 Å
1.01 Å/pix.
x 240 pix.
= 242.4 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.01 Å
Density
Contour LevelBy AUTHOR: 2.58 / Movie #1: 2.58
Minimum - Maximum-1.4834414 - 6.6500583
Average (Standard dev.)0.045202695 (±0.6254163)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions240240240
Spacing240240240
CellA=B=C: 242.4 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.011.011.01
M x/y/z240240240
origin x/y/z0.0000.0000.000
length x/y/z242.400242.400242.400
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ240240240
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS240240240
D min/max/mean-1.4836.6500.045

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Supplemental data

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Sample components

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Entire Human GluN1/GluN2A NMDA receptors in the glutamate/glycine bound ...

EntireName: Human GluN1/GluN2A NMDA receptors in the glutamate/glycine bound state at pH 6.3, Class II
Details: with the presence of Glycine,L-glutamate and EDTA / Number of components: 3

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Component #1: protein, Human GluN1/GluN2A NMDA receptors in the glutamate/glyci...

ProteinName: Human GluN1/GluN2A NMDA receptors in the glutamate/glycine bound state at pH 6.3, Class II
Details: with the presence of Glycine,L-glutamate and EDTA / Recombinant expression: No
MassTheoretical: 380 kDa
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Homo sapiens (human) / Vector: pEG-Bacmam / Cell of expression system: HEK293S GnTl-

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Component #2: protein, Glutamate receptor ionotropic, NMDA 1

ProteinName: Glutamate receptor ionotropic, NMDA 1 / Details: 2 mM Glycine / Number of Copies: 2 / Recombinant expression: No
MassTheoretical: 95.336219 kDa
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Homo sapiens (human)

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Component #3: protein, Glutamate receptor ionotropic, NMDA 2A

ProteinName: Glutamate receptor ionotropic, NMDA 2A / Details: 2 mM L-Glutamate / Number of Copies: 2 / Recombinant expression: No
MassTheoretical: 94.192172 kDa
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Homo sapiens (human)

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Experimental details

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Sample preparation

SpecimenSpecimen state: Particle / Method: cryo EM
Sample solutionSpecimen conc.: 3.5 mg/mL / Buffer solution: Solutions were made fresh. / pH: 6.3
Support film15 mA
VitrificationInstrument: FEI VITROBOT MARK II / Cryogen name: ETHANE / Temperature: 291 K / Humidity: 100 %
Details: blot for 2 seconds before plunging in liquid ethane.

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
ImagingMicroscope: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Electron dose: 56 e/Å2 / Illumination mode: FLOOD BEAM
LensImaging mode: BRIGHT FIELD
Specimen HolderModel: OTHER
CameraDetector: GATAN K2 SUMMIT (4k x 4k)

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Image processing

ProcessingMethod: single particle reconstruction / Number of projections: 148840
3D reconstructionResolution: 5.5 Å / Resolution method: FSC 0.143 CUT-OFF

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Atomic model buiding

Modeling #1Refinement protocol: rigid body
Input PDB model: 4PE5, 5TQ0, 5H8F, 4PE5, 4PE5, 4PE5, 5H8F
Chain ID: A, B, A, B, C, D, B
Output model

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