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- EMDB-8098: Cryo-EM structure of GluN1/GluN2B NMDA receptor in the glutamate/... -

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Basic information

Entry
Database: EMDB / ID: EMD-8098
TitleCryo-EM structure of GluN1/GluN2B NMDA receptor in the glutamate/glycine/Ro25-6981-bound conformation
Map data
Sample
  • Organelle or cellular component: GluN1-GluN2B receptor in the complex with glycine and glutamate plus allosteric inhibitor Ro25-6981
    • Protein or peptide: N-methyl-D-aspartate receptor subunit NR1-8a
    • Protein or peptide: Ionotropic glutamate receptor subunit NR2B
    • Ligand: GLYCINE
    • Ligand: 4-[(1R,2S)-3-(4-benzylpiperidin-1-yl)-1-hydroxy-2-methylpropyl]phenol
    • Ligand: GLUTAMIC ACID
Keywordsligand-gated ion channel / synaptic transmission / SIGNALING PROTEIN
Function / homology
Function and homology information


NMDA glutamate receptor activity / NMDA selective glutamate receptor complex / response to zinc ion / response to magnesium ion / late endosome / postsynaptic membrane / lysosome / metal ion binding / plasma membrane
Similarity search - Function
Glutamate [NMDA] receptor, epsilon subunit, C-terminal / N-methyl D-aspartate receptor 2B3 C-terminus / : / : / Ionotropic glutamate receptor, metazoa / Ligated ion channel L-glutamate- and glycine-binding site / Ionotropic glutamate receptor, L-glutamate and glycine-binding domain / Ligated ion channel L-glutamate- and glycine-binding site / Ligand-gated ion channel / : ...Glutamate [NMDA] receptor, epsilon subunit, C-terminal / N-methyl D-aspartate receptor 2B3 C-terminus / : / : / Ionotropic glutamate receptor, metazoa / Ligated ion channel L-glutamate- and glycine-binding site / Ionotropic glutamate receptor, L-glutamate and glycine-binding domain / Ligated ion channel L-glutamate- and glycine-binding site / Ligand-gated ion channel / : / 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 / Glutamate receptor ionotropic, NMDA 1
Similarity search - Component
Biological speciesXenopus laevis (African clawed frog)
Methodsingle particle reconstruction / cryo EM / Resolution: 7.5 Å
AuthorsZhu S / Stein AR
CitationJournal: Cell / Year: 2016
Title: Mechanism of NMDA Receptor Inhibition and Activation.
Authors: Shujia Zhu / Richard A Stein / Craig Yoshioka / Chia-Hsueh Lee / April Goehring / Hassane S Mchaourab / Eric Gouaux /
Abstract: N-methyl-D-aspartate receptors (NMDARs) are glutamate-gated, calcium-permeable ion channels that mediate synaptic transmission and underpin learning and memory. NMDAR dysfunction is directly ...N-methyl-D-aspartate receptors (NMDARs) are glutamate-gated, calcium-permeable ion channels that mediate synaptic transmission and underpin learning and memory. NMDAR dysfunction is directly implicated in diseases ranging from seizure to ischemia. Despite its fundamental importance, little is known about how the NMDAR transitions between inactive and active states and how small molecules inhibit or activate ion channel gating. Here, we report electron cryo-microscopy structures of the GluN1-GluN2B NMDA receptor in an ensemble of competitive antagonist-bound states, an agonist-bound form, and a state bound with agonists and the allosteric inhibitor Ro25-6981. Together with double electron-electron resonance experiments, we show how competitive antagonists rupture the ligand binding domain (LBD) gating "ring," how agonists retain the ring in a dimer-of-dimers configuration, and how allosteric inhibitors, acting within the amino terminal domain, further stabilize the LBD layer. These studies illuminate how the LBD gating ring is fundamental to signal transduction and gating in NMDARs.
History
DepositionApr 8, 2016-
Header (metadata) releaseApr 20, 2016-
Map releaseApr 20, 2016-
UpdateMar 6, 2024-
Current statusMar 6, 2024Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.039
  • Imaged by UCSF Chimera
  • Download
  • Surface view colored by height
  • Surface level: 0.039
  • Imaged by UCSF Chimera
  • Download
  • Surface view with fitted model
  • Atomic models: PDB-5iov
  • Surface level: 0.039
  • Imaged by UCSF Chimera
  • Download
Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_8098.png

Downloads & links

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Map

FileDownload / File: emd_8098.map.gz / Format: CCP4 / Size: 32.4 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.07 Å/pix.
x 191 pix.
= 204.37 Å		1.07 Å/pix.
x 201 pix.
= 215.07 Å		1.07 Å/pix.
x 221 pix.
= 236.47 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

generated in cubic-lattice coordinate

Voxel sizeX=Y=Z: 1.07 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy EMDB: 0.035 / Movie #1: 0.039
Minimum - Maximum-0.042173214 - 0.12012543
Average (Standard dev.)0.0029987372 (±0.010199194)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions201221191
Spacing221201191
CellA: 236.47003 Å / B: 215.07004 Å / C: 204.37003 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.071.071.07
M x/y/z221201191
origin x/y/z0.0000.0000.000
length x/y/z236.470215.070204.370
α/β/γ90.00090.00090.000
start NX/NY/NZ-25-77-48
NX/NY/NZ899896
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS221201191
D min/max/mean-0.0420.1200.003

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Supplemental data

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Sample components

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Entire : GluN1-GluN2B receptor in the complex with glycine and glutamate p...

EntireName: GluN1-GluN2B receptor in the complex with glycine and glutamate plus allosteric inhibitor Ro25-6981
Components
  • Organelle or cellular component: GluN1-GluN2B receptor in the complex with glycine and glutamate plus allosteric inhibitor Ro25-6981
    • Protein or peptide: N-methyl-D-aspartate receptor subunit NR1-8a
    • Protein or peptide: Ionotropic glutamate receptor subunit NR2B
    • Ligand: GLYCINE
    • Ligand: 4-[(1R,2S)-3-(4-benzylpiperidin-1-yl)-1-hydroxy-2-methylpropyl]phenol
    • Ligand: GLUTAMIC ACID

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Supramolecule #1: GluN1-GluN2B receptor in the complex with glycine and glutamate p...

SupramoleculeName: GluN1-GluN2B receptor in the complex with glycine and glutamate plus allosteric inhibitor Ro25-6981
type: organelle_or_cellular_component / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Xenopus laevis (African clawed frog)

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Macromolecule #1: N-methyl-D-aspartate receptor subunit NR1-8a

MacromoleculeName: N-methyl-D-aspartate receptor subunit NR1-8a / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Xenopus laevis (African clawed frog)
Molecular weightTheoretical: 92.651234 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: DPKIVNIGAV LSTKKHEQIF REAVNQANFF HFTRKIQLNA TSVTHRPNAI QMALSVCEDL ISSQVYAILV SHPPAPTDHL TPTPISYTA GFYRIPVIGL TTRMSIYSDK SIHLSFLRTV PPYSHQALVW FEMMRLFNWN HVILIVSDDH EGRAAQKKLE T LLEEKESK ...String:
DPKIVNIGAV LSTKKHEQIF REAVNQANFF HFTRKIQLNA TSVTHRPNAI QMALSVCEDL ISSQVYAILV SHPPAPTDHL TPTPISYTA GFYRIPVIGL TTRMSIYSDK SIHLSFLRTV PPYSHQALVW FEMMRLFNWN HVILIVSDDH EGRAAQKKLE T LLEEKESK ADKVLQFEPG TKNLTALLLE AKELEARVII LSASEDDATA VYKSAAMLDM TGAGYVWLVG EREISGSALR YA PDGIIGL QLINGKNESA HISDAVAVVA QAIHELFEME QITDPPRGCV GNTNIWKTGP LFKRVLMSSK YPDGVTGRIE FNE DGDRKF AQYSIMNLQN RKLVQVGIFD GSYIIQNDRK IIWPGGETER PQGYQMSTRL KIVTIHQEPF VYVRPTTSDG TCRE EYTIN GDPIKKVICN GPDETIPGRP TVPQCCYGFC VDLLIKLARE MDFTYEVHLV ADGKFGTQER VNNSNAAAWN GMMGE LLSG QADMIVAPLT INNERAQYIE FSKPFKYQGL TILVKKEIPR STLDSFMQPF QSTLWLLVGL SVHVVAVMLY LLDRFS PFG RFEDALTLSS AMWFSWRVLL NSGLGEGAPR SFSARILGMV WAGFAMIIVA SYTANLAAFL VLRRPEERIT GINDPRL RN PSDKFIYATV KQSSVDIYFR RQVELSTMYR HMEKHNYESA AEAIQAVRDN KLHAFIWDSA VLEFEASQKC DLVTTGEL F FRSGFGIGMR KDSPWKQEVS LNILKSHENG FMEELDKTWV RYQECDSRSN APATLTFENM AGVFMLVAGG IVAGIFLIF IEIAYKSRAE AKRMKGLEVL FQ

UniProtKB: Glutamate receptor ionotropic, NMDA 1

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Macromolecule #2: Ionotropic glutamate receptor subunit NR2B

MacromoleculeName: Ionotropic glutamate receptor subunit NR2B / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Xenopus laevis (African clawed frog)
Molecular weightTheoretical: 93.234742 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MRPTEACCYL KISLIILFYS RAYAQKHPNM DIAVILVGTT EEVAIKDVHE KDDFHHLPVT PRVELVTMQE SDPKSIITRI CDLMSDKKV QGVVFGDDTD QEAIAQILDF ISVQTLTPIL GIHGGSSMIM ADKEEASMFF QFGPSIEQQA SVMLNIMEEY D WYIFSIVT ...String:
MRPTEACCYL KISLIILFYS RAYAQKHPNM DIAVILVGTT EEVAIKDVHE KDDFHHLPVT PRVELVTMQE SDPKSIITRI CDLMSDKKV QGVVFGDDTD QEAIAQILDF ISVQTLTPIL GIHGGSSMIM ADKEEASMFF QFGPSIEQQA SVMLNIMEEY D WYIFSIVT TYFPGYQDFE NKVRSTIENS FVGWELEEVI HLDMSLDDID SKIQNQLKKL QSPVILLYCT KEEATYIFEV AH SVGLTGY GFTWIVPSLV AGDTDTVPDE FPTGLISVSY DEWDYDLPAR VRDGIAIITT AASTMLSEHN SIPQSKSSCN NIQ ESRVYE AHMLKRYLIN VTFEGRDLSF SEDGYQMHPK LVIILLNQER KWERVGKYKD RSLKMWPVFD LYPNSEEHKD EHLS IVTLE EAPFVIVEDV DPLSGTCMRN TVPCRKQIRP ENRTEEGGNY IKRCCKGFCI DILKKIAKTV KFTYDLYLVT NGKHG KKIN GVWNGMIGEV VTKRAYMAVG SLTINEERSE VVDFSVPFIE TGISVMVSRS NGTVSPSAFL EPFSADVWVM MFVMLL IVS AVAVFVFEYF SPVGYNGPSF TIGKAIWLLW GLVFNNSLPV QNPKGTTSKI MVSVWAFFAV IFLASYTANL AAFMIQR RY VDQVSGLSDK KFQRPNDFSP AFRFGTVPNG STERNIRNNY LEMHSYMVKF NQRSVQDALL SLKSGKLDAF IYDAAVLN Y MAGRDEGCKL VTIGSGKVFA TTGYGIAIQK DSGWKRQVDL AILQLFGDGE MEELEALWLT GICHNEKNEV MSSQLDIDN MAGVFYMLAA AMALSLITFI MEHLF

UniProtKB: Glutamate receptor ionotropic, NMDA 2B

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Macromolecule #3: GLYCINE

MacromoleculeName: GLYCINE / type: ligand / ID: 3 / Number of copies: 2 / Formula: GLY
Molecular weightTheoretical: 75.067 Da
Chemical component information

ChemComp-GLY:
GLYCINE

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Macromolecule #4: 4-[(1R,2S)-3-(4-benzylpiperidin-1-yl)-1-hydroxy-2-methylpropyl]phenol

MacromoleculeName: 4-[(1R,2S)-3-(4-benzylpiperidin-1-yl)-1-hydroxy-2-methylpropyl]phenol
type: ligand / ID: 4 / Number of copies: 2 / Formula: QEM
Molecular weightTheoretical: 339.471 Da
Chemical component information

ChemComp-QEM:
4-[(1R,2S)-3-(4-benzylpiperidin-1-yl)-1-hydroxy-2-methylpropyl]phenol

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Macromolecule #5: GLUTAMIC ACID

MacromoleculeName: GLUTAMIC ACID / type: ligand / ID: 5 / Number of copies: 2 / Formula: GLU
Molecular weightTheoretical: 147.129 Da
Chemical component information

ChemComp-GLU:
GLUTAMIC ACID

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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

Concentration4 mg/mL
BufferpH: 6.5
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 18 K / Instrument: FEI VITROBOT MARK III

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: SUPER-RESOLUTION / Average electron dose: 10.2 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 0.01 mm / Nominal defocus max: 3.5 µm / Nominal defocus min: 1.5 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 186539
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

4tlm

Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 7.5 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 87851
Initial angle assignmentType: PROJECTION MATCHING
Final angle assignmentType: PROJECTION MATCHING

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