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- EMDB-9717: Structure of the human GluN1/GluN2A NMDA receptor in the glutamat... -

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Entry
Database: EMDB / ID: 9717
TitleStructure of the human GluN1/GluN2A NMDA receptor in the glutamate/glycine-bound state at pH 6.3, Class III
Map data
SampleHuman GluN1/GluN2A NMDA receptors in the glutamate/glycine bound state at pH 6.3, Class III
  • (Glutamate receptor ionotropic, NMDA ...) x 2
Function / homologyIonotropic glutamate receptor, metazoa / CREB1 phosphorylation through the activation of CaMKII/CaMKK/CaMKIV cascasde / N-methyl D-aspartate receptor 2B3 C-terminus / Calmodulin-binding domain C0 of NMDA receptor NR1 subunit / Ligated ion channel L-glutamate- and glycine-binding site / EPHB-mediated forward signaling / Receptor, ligand binding region / Unblocking of NMDA receptors, glutamate binding and activation / Receptor family ligand binding region / Ligand-gated ion channel ...Ionotropic glutamate receptor, metazoa / CREB1 phosphorylation through the activation of CaMKII/CaMKK/CaMKIV cascasde / N-methyl D-aspartate receptor 2B3 C-terminus / Calmodulin-binding domain C0 of NMDA receptor NR1 subunit / Ligated ion channel L-glutamate- and glycine-binding site / EPHB-mediated forward signaling / Receptor, ligand binding region / Unblocking of NMDA receptors, glutamate binding and activation / Receptor family ligand binding region / Ligand-gated ion channel / Periplasmic binding protein-like I / Ionotropic glutamate receptor, L-glutamate and glycine-binding domain / Glutamate [NMDA] receptor, epsilon subunit, C-terminal / Ras activation upon Ca2+ influx through NMDA receptor / Synaptic adhesion-like molecules / Ionotropic glutamate receptor / RAF/MAP kinase cascade / MECP2 regulates neuronal receptors and channels / Calmodulin-binding domain C0, NMDA receptor, NR1 subunit / Neurexins and neuroligins / response to glycine / propylene metabolic process / pons maturation / protein localization to postsynaptic membrane / directional locomotion / excitatory chemical synaptic transmission / regulation of respiratory gaseous exchange / conditioned taste aversion / olfactory learning / male mating behavior / serotonin metabolic process / glutamate receptor signaling pathway / startle response / regulation of synapse assembly / sleep / glutamate-gated calcium ion channel activity / neurotransmitter binding / calcium ion transmembrane import into cytosol / cation transport / neurogenesis / respiratory gaseous exchange / calcium ion homeostasis / activation of cysteine-type endopeptidase activity / glycine binding / NMDA glutamate receptor activity / glutamate binding / NMDA selective glutamate receptor complex / regulation of dendrite morphogenesis / dopamine metabolic process / suckling behavior / synaptic membrane / positive regulation of cysteine-type endopeptidase activity / social behavior / positive regulation of reactive oxygen species biosynthetic process / regulation of axonogenesis / synaptic transmission, glutamatergic / postsynaptic density membrane / positive regulation of calcium ion transport into cytosol / response to morphine / excitatory synapse / long-term memory / excitatory postsynaptic potential / synaptic cleft / positive regulation of excitatory postsynaptic potential / sensory perception of pain / prepulse inhibition / adult locomotory behavior / regulation of membrane potential / cerebral cortex development / integral component of postsynaptic density membrane / regulation of sensory perception of pain / transmitter-gated ion channel activity involved in regulation of postsynaptic membrane potential / response to amphetamine / regulation of synaptic plasticity / visual learning / long-term synaptic potentiation / ionotropic glutamate receptor signaling pathway / memory / regulation of long-term neuronal synaptic plasticity / positive regulation of long-term synaptic potentiation / presynaptic membrane / terminal bouton / synaptic vesicle / ephrin receptor signaling pathway / negative regulation of protein catabolic process / protein heterotetramerization / brain development / postsynaptic membrane / response to wounding / learning or memory / Ras guanyl-nucleotide exchange factor activity / chemical synaptic transmission / amyloid-beta binding / negative regulation of neuron apoptotic process / calmodulin binding / response to ethanol / dendritic spine / MAPK cascade / postsynaptic density / protein-containing complex binding
Function and homology information
SourceHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / 7.8 Å resolution
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: 6irh

SummaryFull reportAbout validation report
DateDeposition: Nov 12, 2018 / Header (metadata) release: Jan 16, 2019 / Map release: Jan 16, 2019 / Last update: Jan 16, 2019

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Structure visualization

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  • Surface view with section colored by density value
  • Surface level: 3
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 3
  • Imaged by UCSF Chimera
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  • Map surface with fitted models
  • Surface level: 3
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

Downloads & links

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Map

Fileemd_9717.map.gz (map file in CCP4 format, 55297 KB)
Projections & slices

Image control

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

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel size
XYZ
EMDB info.1.3071.3071.307
CCP4 map header1.011.011.01
EM Navigator Movie #11.011.011.01
Density
Contour Level:3.0 (by author), 3 (movie #1):
Minimum - Maximum-1.433257 - 7.243222
Average (Standard dev.)0.048366997 (0.74590117)
Details

EMDB XML:

Space Group Number1
Map Geometry
Axis orderXYZ
Dimensions240240240
Origin0.00.00.0
Limit239.0239.0239.0
Spacing240240240
CellA=B=C: 313.68002 Å
α=β=γ: 90.0 deg.

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-1.4337.2430.048

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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 III
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 III
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: 86215
3D reconstructionResolution: 7.8 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
Chain ID: A, B, C, D, B, A, B
Output model

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