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

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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
Sample
  • Complex: Human GluN1/GluN2A NMDA receptors in the glutamate/glycine bound state at pH 6.3, Class II
    • Protein or peptide: Glutamate receptor ionotropic, NMDA 1
    • Protein or peptide: Glutamate receptor ionotropic, NMDA 2A
Keywordsionotropic glutamate receptors / NMDA receptors / synaptic protein / MEMBRANE PROTEIN
Function / homology
Function and homology information


neurotransmitter receptor complex / excitatory chemical synaptic transmission / directional locomotion / serotonin metabolic process / Synaptic adhesion-like molecules / protein localization to postsynaptic membrane / response to glycine / propylene metabolic process / sleep / regulation of monoatomic cation transmembrane transport ...neurotransmitter receptor complex / excitatory chemical synaptic transmission / directional locomotion / serotonin metabolic process / Synaptic adhesion-like molecules / protein localization to postsynaptic membrane / response to glycine / propylene metabolic process / sleep / regulation of monoatomic cation transmembrane transport / Assembly and cell surface presentation of NMDA receptors / NMDA glutamate receptor activity / Neurexins and neuroligins / transmitter-gated monoatomic ion channel activity / NMDA selective glutamate receptor complex / ligand-gated sodium channel activity / glutamate receptor signaling pathway / calcium ion transmembrane import into cytosol / glutamate binding / protein heterotetramerization / glycine binding / positive regulation of reactive oxygen species biosynthetic process / positive regulation of calcium ion transport into cytosol / startle response / Negative regulation of NMDA receptor-mediated neuronal transmission / dopamine metabolic process / monoatomic ion channel complex / Unblocking of NMDA receptors, glutamate binding and activation / monoatomic cation transmembrane transport / regulation of neuronal synaptic plasticity / monoatomic cation transport / Long-term potentiation / positive regulation of excitatory postsynaptic potential / excitatory synapse / ligand-gated monoatomic ion channel activity / synaptic cleft / calcium ion homeostasis / MECP2 regulates neuronal receptors and channels / glutamate-gated calcium ion channel activity / sensory perception of pain / EPHB-mediated forward signaling / cytoplasmic vesicle membrane / response to amphetamine / sodium ion transmembrane transport / ionotropic glutamate receptor signaling pathway / Ras activation upon Ca2+ influx through NMDA receptor / positive regulation of synaptic transmission, glutamatergic / transmitter-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential / regulation of membrane potential / excitatory postsynaptic potential / synaptic transmission, glutamatergic / neurogenesis / long-term synaptic potentiation / synaptic membrane / protein catabolic process / postsynaptic density membrane / visual learning / terminal bouton / brain development / negative regulation of protein catabolic process / regulation of synaptic plasticity / response to wounding / calcium ion transmembrane transport / memory / synaptic vesicle / signaling receptor activity / amyloid-beta binding / presynaptic membrane / RAF/MAP kinase cascade / chemical synaptic transmission / response to ethanol / postsynaptic membrane / dendritic spine / learning or memory / calmodulin binding / postsynaptic density / neuron projection / positive regulation of apoptotic process / response to xenobiotic stimulus / dendrite / calcium ion binding / synapse / endoplasmic reticulum membrane / protein-containing complex binding / glutamatergic synapse / cell surface / positive regulation of transcription by RNA polymerase II / zinc ion binding / plasma membrane / cytoplasm
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 2A
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 5.5 Å
AuthorsZhang J / Chang S
Funding support China, 5 items
OrganizationGrant numberCountry
National Basic Research Program of China (973 Program)2017YFA0504803 China
National Basic Research Program of China (973 Program)2018YFA0507700 China
National Basic Research Program of China (973 Program)2017YFA0505700 China
National Natural Science Foundation of China31771115 China
Chinese Academy of SciencesXDBS32020000 China
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.
History
DepositionNov 12, 2018-
Header (metadata) releaseJan 16, 2019-
Map releaseJan 16, 2019-
UpdateOct 23, 2024-
Current statusOct 23, 2024Processing 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
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  • 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

emd_9716.png

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

Histogram

Histogram (log scale)
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
Components
  • Complex: Human GluN1/GluN2A NMDA receptors in the glutamate/glycine bound state at pH 6.3, Class II
    • Protein or peptide: Glutamate receptor ionotropic, NMDA 1
    • Protein or peptide: Glutamate receptor ionotropic, NMDA 2A

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Supramolecule #1: Human GluN1/GluN2A NMDA receptors in the glutamate/glycine bound ...

SupramoleculeName: Human GluN1/GluN2A NMDA receptors in the glutamate/glycine bound state at pH 6.3, Class II
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all / Details: with the presence of Glycine,L-glutamate and EDTA
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 380 KDa

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Macromolecule #1: Glutamate receptor ionotropic, NMDA 1

MacromoleculeName: Glutamate receptor ionotropic, NMDA 1 / type: protein_or_peptide / ID: 1 / Details: 2 mM Glycine / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 95.336219 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MSTMRLLTLA LLFSCSVARA ACDPKIVNIG AVLSTRKHEQ MFREAVNQAN KRHGSWKIQL NATSVTHKPN AIQMALSVCE DLISSQVYA ILVSHPPTPN DHFTPTPVSY TAGFYRIPVL GLTTRMSIYS DKSIHLSFLR TVPPYSHQSS VWFEMMRVYS W NHIILLVS ...String:
MSTMRLLTLA LLFSCSVARA ACDPKIVNIG AVLSTRKHEQ MFREAVNQAN KRHGSWKIQL NATSVTHKPN AIQMALSVCE DLISSQVYA ILVSHPPTPN DHFTPTPVSY TAGFYRIPVL GLTTRMSIYS DKSIHLSFLR TVPPYSHQSS VWFEMMRVYS W NHIILLVS DDHEGRAAQK RLETLLEERE SKAEKVLQFD PGTKNVTALL MEAKELEARV IILSASEDDA ATVYRAAAML NM TGSGYVW LVGEREISGN ALRYAPDGIL GLQLINGKNE SAHISDAVGV VAQAVHELLE KENITDPPRG CVGNTNIWKT GPL FKRVLM SSKYADGVTG RVEFNEDGDR KFANYSIMNL QNRKLVQVGI YNGTHVIPND RKIIWPGGET EKPRGYQMST RLKI VTIHQ EPFVYVKPTL SDGTCKEEFT VNGDPVKKVI CTGPNDTSPG SPRHTVPQCC YGFCIDLLIK LARTMNFTYE VHLVA DGKF GTQERVNNSN KKEWNGMMGE LLSGQADMIV APLTINNERA QYIEFSKPFK YQGLTILVKK EIPRSTLDSF MQPFQS TLW LLVGLSVHVV AVMLYLLDRF SPFGRFKVNS EEEEEDALTL SSAMWFSWRV LLNSGIGEGA PRSFSARILG MVWAGFA MI IVASYTANLA AFLVLDRPEE RITGINDPRL RNPSDKFIYA TVKQSSVDIY FRRQVELSTM YRHMEKHNYE SAAEAIQA V RDNKLHAFIW DSAVLEFEAS QKCDLVTTGE LFFRSGFGIG MRKDSPWKQN VSLSILKSHE NGFMEDLDKT WVRYQECDS RSNAPATLTF ENMAGVFMLV AGGIVAGIFL IFIEIAYKRH KDARRKQ

UniProtKB: Glutamate receptor ionotropic, NMDA 1

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Macromolecule #2: Glutamate receptor ionotropic, NMDA 2A

MacromoleculeName: Glutamate receptor ionotropic, NMDA 2A / type: protein_or_peptide / ID: 2 / Details: 2 mM L-Glutamate / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 94.192172 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MGRVGYWTLL VLPALLVWRG PAPSAAAEKG PPALNIAVML GHSHDVTERE LRTLWGPEQA AGLPLDVNVV ALLMNRTDPK SLITHVCDL MSGARIHGLV FGDDTDQEAV AQMLDFISSH TFVPILGIHG GASMIMADKD PTSTFFQFGA SIQQQATVML K IMQDYDWH ...String:
MGRVGYWTLL VLPALLVWRG PAPSAAAEKG PPALNIAVML GHSHDVTERE LRTLWGPEQA AGLPLDVNVV ALLMNRTDPK SLITHVCDL MSGARIHGLV FGDDTDQEAV AQMLDFISSH TFVPILGIHG GASMIMADKD PTSTFFQFGA SIQQQATVML K IMQDYDWH VFSLVTTIFP GYREFISFVK TTVDNSFVGW DMQNVITLDT SFEDAKTQVQ LKKIHSSVIL LYCSKDEAVL IL SEARSLG LTGYDFFWIV PSLVSGNTEL IPKEFPSGLI SVSYDDWDYS LEARVRDGIG ILTTAASSML EKFSYIPEAK ASC YGQMER PEVPMHTLHP FMVNVTWDGK DLSFTEEGYQ VHPRLVVIVL NKDREWEKVG KWENHTLSLR HAVWPRYKSF SDCE PDDNH LSIVTLEEAP FVIVEDIDPL TETCVRNTVP CRKFVKINNS TNEGMNVKKC CKGFCIDILK KLSRTVKFTY DLYLV TNGK HGKKVNNVWN GMIGEVVYQR AVMAVGSLTI NEERSEVVDF SVPFVETGIS VMVSRSNGTV SPSAFLEPFS ASVWVM MFV MLLIVSAIAV FVFEYFSPVG YNRNLAKGKA PHGPSFTIGK AIWLLWGLVF NNSVPVQNPK GTTSKIMVSV WAFFAVI FL ASYTANLAAF MIQRRFVDQV TGLSDKKFQR PHDYSPPFRF GTVPNGSTER NIRNNYPYMH QYMTKFNQKG VEDALVSL K TGKLDAFIYD AAVLNYKAGR DEGCKLVTIG SGYIFATTGY GIALQKGSPW KRQIDLALLQ FVGDGEMEEL ETLWLTGIC HNEKNEVMSS QLDIDNMAGV FYMLAAAMAL SLITFIWEHL F

UniProtKB: Glutamate receptor ionotropic, NMDA 2A

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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

Concentration3.5 mg/mL
BufferpH: 6.3
Component:
ConcentrationFormulaName
150.0 mMNaClsodium chloride
20.0 mMC6H13NO4SMES
0.05 mM(HO2CCH2)2NCH2CH2N(CH2CO2H)2EDTA
0.005 mMC31H50O4(C4H11NO3)Cholesteryl Hemisuccinate Tris Salt
0.001 g/mLC56H92O29Digitonin
0.1 mMC32H58N2O8SCHAPSO
2.0 mMNH2CH2COOHGlycine
2.0 mMC5H8NNaO4(xH2O)L-Glutamic acid monosodium salt hydrate

Details: Solutions were made fresh.
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 200 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 45 sec. / Pretreatment - Atmosphere: AIR / Pretreatment - Pressure: 260.0 kPa / Details: 15 mA
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 291 K / Instrument: FEI VITROBOT MARK II
Details: blot for 2 seconds before plunging in liquid ethane.
DetailsTetrameric GluN1/GluN2A NMDA receptors

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: SUPER-RESOLUTION / Digitization - Frames/image: 1-40 / Number grids imaged: 4 / Average exposure time: 12.0 sec. / Average electron dose: 56.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 722287
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 5.5 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 148840
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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Atomic model buiding 1

Initial model
PDB IDChain

4pe5

chain_id: A, source_name: PDB, initial_model_type: experimental model

5tq0

chain_id: B, source_name: PDB, initial_model_type: experimental model

5h8f

chain_id: A, source_name: PDB, initial_model_type: experimental model

4pe5

chain_id: B, source_name: PDB, initial_model_type: experimental model

4pe5

chain_id: C, source_name: PDB, initial_model_type: experimental model

4pe5

chain_id: D, source_name: PDB, initial_model_type: experimental model

5h8f

chain_id: B, source_name: PDB, initial_model_type: experimental model
RefinementProtocol: RIGID BODY FIT
Output model

PDB-6irg:
Structure of the human GluN1/GluN2A NMDA receptor in the glutamate/glycine-bound state at pH 6.3, Class II

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