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- EMDB-3356: Activation of NMDA receptors and the mechanism of inhibition by i... -

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Basic information

Entry
Database: EMDB / ID: EMD-3356
TitleActivation of NMDA receptors and the mechanism of inhibition by ifenprodil - Class Y
Map dataClass Y, unsharpened, unmasked map
Sample
  • Sample: NMDA Receptor
  • Protein or peptide: N-methyl-D-aspartate receptor GluN1
  • Protein or peptide: N-methyl-D-aspartate receptor GluN2B
KeywordsNMDA receptor / glutamate receptor / GluN1 / GluN2B / ion channel
Function / homology
Function and homology information


neurotransmitter receptor activity involved in regulation of postsynaptic membrane potential / cellular response to curcumin / cellular response to corticosterone stimulus / cellular response to magnesium starvation / regulation of postsynaptic cytosolic calcium ion concentration / NMDA selective glutamate receptor signaling pathway / sensory organ development / sensitization / pons maturation / regulation of cell communication ...neurotransmitter receptor activity involved in regulation of postsynaptic membrane potential / cellular response to curcumin / cellular response to corticosterone stimulus / cellular response to magnesium starvation / regulation of postsynaptic cytosolic calcium ion concentration / NMDA selective glutamate receptor signaling pathway / sensory organ development / sensitization / pons maturation / regulation of cell communication / positive regulation of Schwann cell migration / EPHB-mediated forward signaling / Assembly and cell surface presentation of NMDA receptors / neurotransmitter receptor activity involved in regulation of postsynaptic cytosolic calcium ion concentration / olfactory learning / conditioned taste aversion / regulation of protein kinase A signaling / protein localization to postsynaptic membrane / apical dendrite / dendritic branch / regulation of respiratory gaseous exchange / propylene metabolic process / response to glycine / response to other organism / fear response / response to methylmercury / voltage-gated monoatomic cation channel activity / response to morphine / glutamate-gated calcium ion channel activity / positive regulation of cysteine-type endopeptidase activity / cellular response to dsRNA / regulation of monoatomic cation transmembrane transport / response to carbohydrate / interleukin-1 receptor binding / negative regulation of dendritic spine maintenance / cellular response to lipid / positive regulation of glutamate secretion / NMDA glutamate receptor activity / NMDA selective glutamate receptor complex / RAF/MAP kinase cascade / response to growth hormone / Synaptic adhesion-like molecules / parallel fiber to Purkinje cell synapse / calcium ion transmembrane import into cytosol / response to manganese ion / protein heterotetramerization / glutamate binding / positive regulation of reactive oxygen species biosynthetic process / neuromuscular process / regulation of synapse assembly / glycine binding / action potential / positive regulation of calcium ion transport into cytosol / regulation of neuronal synaptic plasticity / male mating behavior / regulation of dendrite morphogenesis / regulation of axonogenesis / receptor clustering / heterocyclic compound binding / suckling behavior / behavioral response to pain / startle response / response to amine / monoatomic cation transmembrane transport / social behavior / ligand-gated monoatomic ion channel activity / small molecule binding / positive regulation of excitatory postsynaptic potential / regulation of MAPK cascade / response to magnesium ion / associative learning / monoatomic cation transport / excitatory synapse / positive regulation of dendritic spine maintenance / extracellularly glutamate-gated ion channel activity / cellular response to organic cyclic compound / neuron development / Unblocking of NMDA receptors, glutamate binding and activation / long-term memory / regulation of postsynaptic membrane potential / glutamate receptor binding / behavioral fear response / D2 dopamine receptor binding / phosphatase binding / multicellular organismal response to stress / calcium ion homeostasis / synaptic cleft / cellular response to manganese ion / prepulse inhibition / positive regulation of synaptic transmission / detection of mechanical stimulus involved in sensory perception of pain / response to mechanical stimulus / response to electrical stimulus / regulation of neuron apoptotic process / presynaptic active zone membrane / response to fungicide / cellular response to forskolin / glutamate-gated receptor activity / monoatomic cation channel activity / sensory perception of pain
Similarity search - Function
Glutamate [NMDA] receptor, epsilon subunit, C-terminal / N-methyl D-aspartate receptor 2B3 C-terminus / Bacterial extracellular solute-binding proteins, family 3 / Solute-binding protein family 3/N-terminal domain of MltF / Ionotropic glutamate receptor, metazoa / Ligated ion channel L-glutamate- and glycine-binding site / : / Ligand-gated ion channel / Ionotropic glutamate receptor, L-glutamate and glycine-binding domain / Ligated ion channel L-glutamate- and glycine-binding site ...Glutamate [NMDA] receptor, epsilon subunit, C-terminal / N-methyl D-aspartate receptor 2B3 C-terminus / Bacterial extracellular solute-binding proteins, family 3 / Solute-binding protein family 3/N-terminal domain of MltF / Ionotropic glutamate receptor, metazoa / Ligated ion channel L-glutamate- and glycine-binding site / : / Ligand-gated ion channel / Ionotropic glutamate receptor, L-glutamate and glycine-binding domain / Ligated ion channel L-glutamate- and glycine-binding site / Ionotropic glutamate receptor / Eukaryotic homologues of bacterial periplasmic substrate binding proteins. / Receptor, ligand binding region / Receptor family ligand binding region / Periplasmic binding protein-like I
Similarity search - Domain/homology
Glutamate receptor ionotropic, NMDA 1 / Glutamate receptor ionotropic, NMDA 2B
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat)
Methodsingle particle reconstruction / cryo EM / Resolution: 6.25 Å
AuthorsTajima N / Karakas E / Grant T / Simorowski N / Diaz-Avalos R / Grigorieff N / Furukawa H
CitationJournal: Nature / Year: 2016
Title: Activation of NMDA receptors and the mechanism of inhibition by ifenprodil.
Authors: Nami Tajima / Erkan Karakas / Timothy Grant / Noriko Simorowski / Ruben Diaz-Avalos / Nikolaus Grigorieff / Hiro Furukawa /
Abstract: The physiology of N-methyl-d-aspartate (NMDA) receptors is fundamental to brain development and function. NMDA receptors are ionotropic glutamate receptors that function as heterotetramers composed ...The physiology of N-methyl-d-aspartate (NMDA) receptors is fundamental to brain development and function. NMDA receptors are ionotropic glutamate receptors that function as heterotetramers composed mainly of GluN1 and GluN2 subunits. Activation of NMDA receptors requires binding of neurotransmitter agonists to a ligand-binding domain (LBD) and structural rearrangement of an amino-terminal domain (ATD). Recent crystal structures of GluN1-GluN2B NMDA receptors bound to agonists and an allosteric inhibitor, ifenprodil, represent the allosterically inhibited state. However, how the ATD and LBD move to activate the NMDA receptor ion channel remains unclear. Here we applied X-ray crystallography, single-particle electron cryomicroscopy and electrophysiology to rat NMDA receptors to show that, in the absence of ifenprodil, the bi-lobed structure of GluN2 ATD adopts an open conformation accompanied by rearrangement of the GluN1-GluN2 ATD heterodimeric interface, altering subunit orientation in the ATD and LBD and forming an active receptor conformation that gates the ion channel.
History
DepositionMar 2, 2016-
Header (metadata) releaseApr 6, 2016-
Map releaseMay 11, 2016-
UpdateJun 15, 2016-
Current statusJun 15, 2016Processing site: PDBe / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.038
  • Imaged by UCSF Chimera
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  • Surface view colored by height
  • Surface level: 0.038
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-5fxk
  • Surface level: 0.038
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

image_3356.png

Downloads & links

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Map

FileDownload / File: emd_3356.map.gz / Format: CCP4 / Size: 62.5 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationClass Y, unsharpened, unmasked map
Voxel sizeX=Y=Z: 1.31 Å
Density
Contour LevelBy AUTHOR: 0.038 / Movie #1: 0.038
Minimum - Maximum-0.0173353 - 0.08615234
Average (Standard dev.)-0.00064702 (±0.0065396)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 335.36 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.311.311.31
M x/y/z256256256
origin x/y/z0.0000.0000.000
length x/y/z335.360335.360335.360
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS256256256
D min/max/mean-0.0170.086-0.001

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Supplemental data

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Sample components

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Entire : NMDA Receptor

EntireName: NMDA Receptor
Components
  • Sample: NMDA Receptor
  • Protein or peptide: N-methyl-D-aspartate receptor GluN1
  • Protein or peptide: N-methyl-D-aspartate receptor GluN2B

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Supramolecule #1000: NMDA Receptor

SupramoleculeName: NMDA Receptor / type: sample / ID: 1000
Details: The sample was purified in the presence of agonists Glycine and L-glutamate.
Oligomeric state: One heterotetramer of 2 GluN1 and 2 GluN2B subunits
Number unique components: 2
Molecular weightTheoretical: 370 KDa

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Macromolecule #1: N-methyl-D-aspartate receptor GluN1

MacromoleculeName: N-methyl-D-aspartate receptor GluN1 / type: protein_or_peptide / ID: 1 / Name.synonym: GluN1, NR1 / Number of copies: 2 / Oligomeric state: dimer / Recombinant expression: Yes
Source (natural)Organism: Rattus norvegicus (Norway rat) / synonym: Rat / Location in cell: Plasma membane
Molecular weightTheoretical: 93 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm) / Recombinant strain: Sf9 CRL-1711 / Recombinant cell: Sf9 / Recombinant plasmid: Modified pFL and pUCDM
SequenceUniProtKB: Glutamate receptor ionotropic, NMDA 1

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Macromolecule #2: N-methyl-D-aspartate receptor GluN2B

MacromoleculeName: N-methyl-D-aspartate receptor GluN2B / type: protein_or_peptide / ID: 2 / Name.synonym: GluN2B, NR2B / Number of copies: 2 / Oligomeric state: Dimer / Recombinant expression: Yes
Source (natural)Organism: Rattus norvegicus (Norway rat) / synonym: Rat / Location in cell: Plasma membane
Molecular weightTheoretical: 92 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm) / Recombinant strain: Sf9 CRL-1711 / Recombinant cell: Sf9 / Recombinant plasmid: Modified pFL and pUCDM
SequenceUniProtKB: Glutamate receptor ionotropic, NMDA 2B

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration2 mg/mL
BufferpH: 7
Details: 200 mM NaCl, 20 mM HEPES pH 7.0, 10 mM Glycine, 10 mM L-Glutamate, 0.002% MNG-3
GridDetails: C-flat 1.2/1.3 Cu 400
VitrificationCryogen name: ETHANE / Chamber humidity: 90 % / Instrument: FEI VITROBOT MARK II / Method: 3s Blot time

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsCalibrated magnification: 38168 / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Cs: 2.7 mm / Nominal defocus max: 2.5 µm / Nominal defocus min: 1.0 µm / Nominal magnification: 22500
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Alignment procedureLegacy - Electron beam tilt params: 0
Details21s exposure into 70 frames, with an exposure rate of ~8 electrons/pixel/s on the camera.
DateAug 10, 2015
Image recordingCategory: CCD / Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Number real images: 1200 / Average electron dose: 100 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionDetails: Each Particle
Final reconstructionApplied symmetry - Point group: C2 (2 fold cyclic) / Algorithm: OTHER / Resolution.type: BY AUTHOR / Resolution: 6.25 Å / Resolution method: OTHER / Software - Name: Unblur, CTFFIND4, FREALIGN
Details: The highest resolution included in the refinement was 8A.
Number images used: 15000

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Atomic model buiding 1

Initial modelPDB ID:

4pe5


Chain - #0 - Chain ID: A / Chain - #1 - Chain ID: B / Chain - #2 - Chain ID: C / Chain - #3 - Chain ID: D
SoftwareName: Coot
DetailsThe individual domains were initially fitted using coot and real space refinement was performed using Phenix
RefinementSpace: REAL / Protocol: FLEXIBLE FIT / Target criteria: Real Space
Output model

PDB-5fxk:
GluN1b-GluN2B NMDA receptor structure-Class Y

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