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- EMDB-9147: Diheteromeric NMDA receptor GluN1/GluN2A in the '1-Knuckle' confo... -

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Entry
Database: EMDB / ID: 9147
TitleDiheteromeric NMDA receptor GluN1/GluN2A in the '1-Knuckle' conformation, in complex with glycine and glutamate, in the presence of 1 micromolar zinc chloride, and at pH 6.1
Map dataGluN1/GluN2A diheteromeric NMDAR, at pH 6.1, in 1 micromolar zinc, in the 1-knuckle conformation
SampleDiheteromeric NMDA receptor GluN1/GluN2A in the '1-Knuckle' conformation, in complex with glycine and glutamate, in the presence of 1 micromolar zinc chloride, and at pH 6.1
  • (Glutamate receptor ionotropic, NMDA ...) x 2
  • ligand
Function / homologyEPHB-mediated forward signaling / Receptor family ligand binding region / Receptor, ligand binding region / Glutamate [NMDA] receptor, epsilon subunit, C-terminal / Ionotropic glutamate receptor, metazoa / Ionotropic glutamate receptor / Ligand-gated ion channel / Calmodulin-binding domain C0, NMDA receptor, NR1 subunit / Unblocking of NMDA receptors, glutamate binding and activation / Periplasmic binding protein-like I ...EPHB-mediated forward signaling / Receptor family ligand binding region / Receptor, ligand binding region / Glutamate [NMDA] receptor, epsilon subunit, C-terminal / Ionotropic glutamate receptor, metazoa / Ionotropic glutamate receptor / Ligand-gated ion channel / Calmodulin-binding domain C0, NMDA receptor, NR1 subunit / Unblocking of NMDA receptors, glutamate binding and activation / Periplasmic binding protein-like I / N-methyl D-aspartate receptor 2B3 C-terminus / CREB1 phosphorylation through the activation of CaMKII/CaMKK/CaMKIV cascasde / rt:r-rno-442982: / RAF/MAP kinase cascade / Synaptic adhesion-like molecules / Ionotropic glutamate receptor, L-glutamate and glycine-binding domain / Calmodulin-binding domain C0 of NMDA receptor NR1 subunit / Ligated ion channel L-glutamate- and glycine-binding site / response to ammonium ion / dendritic branch / positive regulation of Schwann cell migration / response to other organism / cellular response to lipid / ligand-gated ion channel activity involved in regulation of presynaptic membrane potential / glutamate-gated calcium ion channel activity / cellular response to dsRNA / neurotransmitter binding / calcium ion transmembrane import into cytosol / action potential / glutamate receptor binding / voltage-gated cation channel activity / cellular response to zinc ion / glycine binding / parallel fiber to Purkinje cell synapse / response to carbohydrate / cellular response to magnesium ion / NMDA glutamate receptor activity / glutamate binding / NMDA selective glutamate receptor complex / synaptic membrane / dendrite membrane / response to methylmercury / positive regulation of cysteine-type endopeptidase activity / positive regulation of reactive oxygen species biosynthetic process / response to manganese ion / spinal cord development / postsynaptic density membrane / response to amine / positive regulation of calcium ion transport into cytosol / response to light stimulus / excitatory synapse / excitatory postsynaptic potential / positive regulation of dendritic spine maintenance / synaptic cleft / positive regulation of excitatory postsynaptic potential / phosphatase binding / response to cocaine / response to fungicide / integral component of postsynaptic density membrane / cerebral cortex development / transmitter-gated ion channel activity involved in regulation of postsynaptic membrane potential / ionotropic glutamate receptor activity / cellular response to growth factor stimulus / long-term synaptic potentiation / ionotropic glutamate receptor signaling pathway / cellular response to amino acid stimulus / cell adhesion molecule binding / hippocampus development / cellular response to manganese ion / positive regulation of cell death / hippocampal mossy fiber to CA3 synapse / memory / integral component of presynaptic membrane / regulation of long-term neuronal synaptic plasticity / presynaptic membrane / terminal bouton / rhythmic process / response to calcium ion / response to organic cyclic compound / protein heterotetramerization / learning or memory / protein tetramerization / chemical synaptic transmission / scaffold protein binding / amyloid-beta binding / ATPase binding / response to ethanol / dendritic spine / postsynaptic density / protein dimerization activity / protein-containing complex binding / cell junction / synapse / neuron projection / response to drug / glutamatergic synapse / neuronal cell body / signaling receptor binding / protein heterodimerization activity / protein kinase binding
Function and homology information
SourceRattus norvegicus (Norway rat)
Methodsingle particle reconstruction / cryo EM / 5.97 Å resolution
AuthorsJalali-Yazdi F / Chowdhury S / Yoshioka C / Gouaux E
CitationJournal: Cell / Year: 2018
Title: Mechanisms for Zinc and Proton Inhibition of the GluN1/GluN2A NMDA Receptor.
Authors: Farzad Jalali-Yazdi / Sandipan Chowdhury / Craig Yoshioka / Eric Gouaux
Abstract: N-methyl-D-aspartate receptors (NMDARs) play essential roles in memory formation, neuronal plasticity, and brain development, with their dysfunction linked to a range of disorders from ischemia to ...N-methyl-D-aspartate receptors (NMDARs) play essential roles in memory formation, neuronal plasticity, and brain development, with their dysfunction linked to a range of disorders from ischemia to schizophrenia. Zinc and pH are physiological allosteric modulators of NMDARs, with GluN2A-containing receptors inhibited by nanomolar concentrations of divalent zinc and by excursions to low pH. Despite the widespread importance of zinc and proton modulation of NMDARs, the molecular mechanism by which these ions modulate receptor activity has proven elusive. Here, we use cryoelectron microscopy to elucidate the structure of the GluN1/GluN2A NMDAR in a large ensemble of conformations under a range of physiologically relevant zinc and proton concentrations. We show how zinc binding to the amino terminal domain elicits structural changes that are transduced though the ligand-binding domain and result in constriction of the ion channel gate.
Validation ReportPDB-ID: 6mm9

SummaryFull reportAbout validation report
DateDeposition: Sep 29, 2018 / Header (metadata) release: Oct 24, 2018 / Map release: Nov 28, 2018 / Last update: Dec 19, 2018

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 3.9
  • Imaged by UCSF Chimera
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  • Surface view colored by height
  • Surface level: 3.9
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: : PDB-6mm9
  • Surface level: 3.9
  • 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_9147.map.gz (map file in CCP4 format, 28312 KB)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
192 pix
1.71 Å/pix.
= 328.32 Å
192 pix
1.71 Å/pix.
= 328.32 Å
192 pix
1.71 Å/pix.
= 328.32 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.71 Å
Density
Contour Level:3.9 (by author), 3.9 (movie #1):
Minimum - Maximum-12.195869 - 21.940761999999999
Average (Standard dev.)-0.00000000000535 (1.0)
Details

EMDB XML:

Space Group Number1
Map Geometry
Axis orderXYZ
Dimensions192192192
Origin0.00.00.0
Limit191.0191.0191.0
Spacing192192192
CellA=B=C: 328.32 Å
α=β=γ: 90.0 deg.

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.711.711.71
M x/y/z192192192
origin x/y/z0.0000.0000.000
length x/y/z328.320328.320328.320
α/β/γ90.00090.00090.000
start NX/NY/NZ
NX/NY/NZ
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS192192192
D min/max/mean-12.19621.941-0.000

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Supplemental data

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Mask #1

Fileemd_9147_msk_1.map
Projections & Slices
AxesZYX
Projections
Slices (1/2)
Density Histograms

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Sample components

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Entire Diheteromeric NMDA receptor GluN1/GluN2A in the '1-Knuckle' confo...

EntireName: Diheteromeric NMDA receptor GluN1/GluN2A in the '1-Knuckle' conformation, in complex with glycine and glutamate, in the presence of 1 micromolar zinc chloride, and at pH 6.1
Details: Sample was heterologously expressed in TSA-201 cells, detergent solubilized, and affinity purified
Number of components: 4

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Component #1: protein, Diheteromeric NMDA receptor GluN1/GluN2A in the '1-Knuck...

ProteinName: Diheteromeric NMDA receptor GluN1/GluN2A in the '1-Knuckle' conformation, in complex with glycine and glutamate, in the presence of 1 micromolar zinc chloride, and at pH 6.1
Details: Sample was heterologously expressed in TSA-201 cells, detergent solubilized, and affinity purified
Recombinant expression: No
MassTheoretical: 500 kDa
SourceSpecies: Rattus norvegicus (Norway rat)
Source (engineered)Expression System: Homo sapiens (human) / Cell of expression system: TSA-201

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

ProteinName: Glutamate receptor ionotropic, NMDA 1 / Number of Copies: 2 / Recombinant expression: No
MassTheoretical: 94.189781 kDa
SourceSpecies: Rattus norvegicus (Norway rat)
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 / Number of Copies: 2 / Recombinant expression: No
MassTheoretical: 93.740352 kDa
SourceSpecies: Rattus norvegicus (Norway rat)
Source (engineered)Expression System: Homo sapiens (human)

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Component #4: ligand, N-ACETYL-D-GLUCOSAMINE

LigandName: N-ACETYL-D-GLUCOSAMINEN-Acetylglucosamine / Number of Copies: 34 / Recombinant expression: No
MassTheoretical: 0.221208 kDa

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Experimental details

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Sample preparation

SpecimenSpecimen state: particle / Method: cryo EM
Sample solutionSpecimen conc.: 4 mg/ml / pH: 6.1
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Temperature: 291 K / Humidity: 100 %
Details: Sample was blotted for 3 seconds at blot force 1..

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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: 52 e/Å2 / Illumination mode: FLOOD BEAM
LensCs: 2.7 mm / Imaging mode: BRIGHT FIELD
Specimen HolderModel: OTHER
CameraDetector: GATAN K2 BASE (4k x 4k)

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Image acquisition

Image acquisitionNumber of digital images: 2163

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Image processing

ProcessingMethod: single particle reconstruction / Applied symmetry: C1 (asymmetric) / Number of projections: 94934
3D reconstructionAlgorithm: FOURIER SPACE / Software: FREALIGN / Resolution: 5.97 Å / Resolution method: FSC 0.143 CUT-OFF
Details: After additional rounds of refinement/further classification, the final particle set for each class was exported to cisTEM (Grant et al., 2018). Further refinement in cisTEM was carried out by masking out the micelle, while keeping the TMD of the receptors for alignment. The area outside of the mask was filtered to 20 A and down-weighted for alignment. For a more accurate and conservative resolution estimate, the cisTEM-generated half-maps were used in RELION to generate the Fourier Shell Coefficient (FSC) curve, and the resolution was calculated at FSC = 0.143 (Scheres and Chen, 2012).

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Atomic model buiding

Modeling #1Refinement protocol: rigid body
Input PDB model: 4PE5, 5TQ0, 5I57, 5UOW
Chain ID: A, B, A, B
Output model

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