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- EMDB-33792: Structure of GluN1a-GluN2D NMDA receptor in complex with agonists... -

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Basic information

Entry
Database: EMDB / ID: EMD-33792
TitleStructure of GluN1a-GluN2D NMDA receptor in complex with agonists glycine and glutamate.
Map data
Sample
  • Complex: NMDA receptor with NMDA 1 incorperated with NMDA 2D
    • Protein or peptide: Glutamate receptor ionotropic, NMDA 1
    • Protein or peptide: Glutamate receptor ionotropic, NMDA 2D
  • Ligand: GLYCINE
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: GLUTAMIC ACID
Keywordsion channel / cryo-EM structure / glutamate receptor / synaptic protein / ELECTRON TRANSPORT
Function / homology
Function and homology information


excitatory chemical synaptic transmission / regulation of sensory perception of pain / Synaptic adhesion-like molecules / cellular response to L-glutamate / propylene metabolic process / response to glycine / voltage-gated monoatomic cation channel activity / glutamate-gated calcium ion channel activity / regulation of monoatomic cation transmembrane transport / Assembly and cell surface presentation of NMDA receptors ...excitatory chemical synaptic transmission / regulation of sensory perception of pain / Synaptic adhesion-like molecules / cellular response to L-glutamate / propylene metabolic process / response to glycine / voltage-gated monoatomic cation channel activity / glutamate-gated calcium ion channel activity / regulation of monoatomic cation transmembrane transport / Assembly and cell surface presentation of NMDA receptors / Neurexins and neuroligins / NMDA glutamate receptor activity / NMDA selective glutamate receptor complex / calcium ion transmembrane import into cytosol / protein heterotetramerization / glutamate binding / positive regulation of reactive oxygen species biosynthetic process / glycine binding / positive regulation of calcium ion transport into cytosol / Negative regulation of NMDA receptor-mediated neuronal transmission / startle response / Unblocking of NMDA receptors, glutamate binding and activation / regulation of neuronal synaptic plasticity / monoatomic cation transmembrane transport / positive regulation of excitatory postsynaptic potential / Long-term potentiation / monoatomic cation transport / ligand-gated monoatomic ion channel activity / excitatory synapse / calcium ion homeostasis / glutamate-gated receptor activity / synaptic cleft / presynaptic active zone membrane / ligand-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential / EPHB-mediated forward signaling / excitatory postsynaptic potential / hippocampal mossy fiber to CA3 synapse / regulation of membrane potential / ionotropic glutamate receptor signaling pathway / Ras activation upon Ca2+ influx through NMDA receptor / positive regulation of synaptic transmission, glutamatergic / adult locomotory behavior / transmitter-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential / synaptic membrane / synaptic transmission, glutamatergic / long-term synaptic potentiation / postsynaptic density membrane / brain development / regulation of synaptic plasticity / visual learning / terminal bouton / synaptic vesicle / signaling receptor activity / amyloid-beta binding / chemical synaptic transmission / RAF/MAP kinase cascade / postsynaptic membrane / response to ethanol / dendritic spine / postsynaptic density / calmodulin binding / neuron projection / dendrite / synapse / glutamatergic synapse / calcium ion binding / protein-containing complex binding / endoplasmic reticulum membrane / cell surface / positive regulation of transcription by RNA polymerase II / plasma membrane / cytoplasm
Similarity search - Function
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. ...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 2D / Glutamate receptor ionotropic, NMDA 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.9 Å
AuthorsZhang JL / Zhu SJ / Zhang M
Funding support China, 5 items
OrganizationGrant numberCountry
STI2030-Major Project2022ZD0212700 China
National Natural Science Foundation of China (NSFC)32221003 China
Lingang LaboratoryLG 202106-02 China
Strategic Priority Research Program of Chinese Academy of ScienceXDBS01020000 China
Shanghai Municipal Science and Technology Major Project2018SHZDZX05 China
CitationJournal: Nat Struct Mol Biol / Year: 2023
Title: Distinct structure and gating mechanism in diverse NMDA receptors with GluN2C and GluN2D subunits.
Authors: Jilin Zhang / Ming Zhang / Qinrui Wang / Han Wen / Zheyi Liu / Fangjun Wang / Yuhang Wang / Fenyong Yao / Nan Song / Zengwei Kou / Yang Li / Fei Guo / Shujia Zhu /
Abstract: N-methyl-D-aspartate (NMDA) receptors are heterotetramers comprising two GluN1 and two alternate GluN2 (N2A-N2D) subunits. Here we report full-length cryo-EM structures of the human N1-N2D di- ...N-methyl-D-aspartate (NMDA) receptors are heterotetramers comprising two GluN1 and two alternate GluN2 (N2A-N2D) subunits. Here we report full-length cryo-EM structures of the human N1-N2D di-heterotetramer (di-receptor), rat N1-N2C di-receptor and N1-N2A-N2C tri-heterotetramer (tri-receptor) at a best resolution of 3.0 Å. The bilobate N-terminal domain (NTD) in N2D intrinsically adopts a closed conformation, leading to a compact NTD tetramer in the N1-N2D receptor. Additionally, crosslinking the ligand-binding domain (LBD) of two N1 protomers significantly elevated the channel open probability (Po) in N1-N2D di-receptors. Surprisingly, the N1-N2C di-receptor adopted both symmetric (minor) and asymmetric (major) conformations, the latter further locked by an allosteric potentiator, PYD-106, binding to a pocket between the NTD and LBD in only one N2C protomer. Finally, the N2A and N2C subunits in the N1-N2A-N2C tri-receptor display a conformation close to one protomer in the N1-N2A and N1-N2C di-receptors, respectively. These findings provide a comprehensive structural understanding of diverse function in major NMDA receptor subtypes.
History
DepositionJul 8, 2022-
Header (metadata) releaseApr 12, 2023-
Map releaseApr 12, 2023-
UpdateAug 2, 2023-
Current statusAug 2, 2023Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_33792.png

Downloads & links

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Map

FileDownload / File: emd_33792.map.gz / Format: CCP4 / Size: 67 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.06 Å
Density
Contour LevelBy AUTHOR: 0.237
Minimum - Maximum-1.5211246 - 2.3744693
Average (Standard dev.)0.006333413 (±0.06177387)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions260260260
Spacing260260260
CellA=B=C: 275.59998 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_33792_msk_1.map
Projections & Slices
AxesZYX

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Half map: #2

Fileemd_33792_half_map_1.map
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Half map: #1

Fileemd_33792_half_map_2.map
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Sample components

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Entire : NMDA receptor with NMDA 1 incorperated with NMDA 2D

EntireName: NMDA receptor with NMDA 1 incorperated with NMDA 2D
Components
  • Complex: NMDA receptor with NMDA 1 incorperated with NMDA 2D
    • Protein or peptide: Glutamate receptor ionotropic, NMDA 1
    • Protein or peptide: Glutamate receptor ionotropic, NMDA 2D
  • Ligand: GLYCINE
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: GLUTAMIC ACID

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Supramolecule #1: NMDA receptor with NMDA 1 incorperated with NMDA 2D

SupramoleculeName: NMDA receptor with NMDA 1 incorperated with NMDA 2D / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human) / Strain: Homo sapiens / Organ: brain / Tissue: brain / Organelle: synapse / Location in cell: plasma membrane
Molecular weightTheoretical: 384.54 kDa/nm

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Macromolecule #1: Glutamate receptor ionotropic, NMDA 1

MacromoleculeName: Glutamate receptor ionotropic, NMDA 1 / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 95.236078 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 SSAMWFSWGV 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 2D

MacromoleculeName: Glutamate receptor ionotropic, NMDA 2D / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 97.226414 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MRGAGGPRGP RGPAKMLLLL ALACASPFPE EAPGPGGAGG PGGGLGGARP LNVALVFSGP AYAAEAARLG PAVAAAVRSP GLDVRPVAL VLNGSDPRSL VLQLCDLLSG LRVHGVVFED DSRAPAVAPI LDFLSAQTSL PIVAVHGGAA LVLTPKEKGS T FLQLGSST ...String:
MRGAGGPRGP RGPAKMLLLL ALACASPFPE EAPGPGGAGG PGGGLGGARP LNVALVFSGP AYAAEAARLG PAVAAAVRSP GLDVRPVAL VLNGSDPRSL VLQLCDLLSG LRVHGVVFED DSRAPAVAPI LDFLSAQTSL PIVAVHGGAA LVLTPKEKGS T FLQLGSST EQQLQVIFEV LEEYDWTSFV AVTTRAPGHR AFLSYIEVLT DGSLVGWEHR GALTLDPGAG EAVLSAQLRS VS AQIRLLF CAREEAEPVF RAAEEAGLTG SGYVWFMVGP QLAGGGGSGA PGEPPLLPGG APLPAGLFAV RSAGWRDDLA RRV AAGVAV VARGAQALLR DYGFLPELGH DCRAQNRTHR GESLHRYFMN ITWDNRDYSF NEDGFLVNPS LVVISLTRDR TWEV VGSWE QQTLRLKYPL WSRYGRFLQP VDDTQHLTVA TLEERPFVIV EPADPISGTC IRDSVPCRSQ LNRTHSPPPD APRPE KRCC KGFCIDILKR LAHTIGFSYD LYLVTNGKHG KKIDGVWNGM IGEVFYQRAD MAIGSLTINE ERSEIVDFSV PFVETG ISV MVARSNGTVS PSAFLEPYSP AVWVMMFVMC LTVVAVTVFI FEYLSPVGYN RSLATGKRPG GSTFTIGKSI WLLWALV FN NSVPVENPRG TTSKIMVLVW AFFAVIFLAS YTANLAAFMI QEEYVDTVSG LSDRKFQRPQ EQYPPLKFGT VPNGSTEK N IRSNYPDMHS YMVRYNQPRV EEALTQLKAG KLDAFIYDAA VLNYMARKDE GCKLVTIGSG KVFATTGYGI ALHKGSRWK RPIDLALLQF LGDDEIEMLE RLWLSGICHN DKIEVMSSKL DIDNMAGVFY MLLVAMGLSL LVFAWEHLVY WRLRHCLGPA ASAWSHPQF EK

UniProtKB: Glutamate receptor ionotropic, NMDA 2D

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Macromolecule #4: GLYCINE

MacromoleculeName: GLYCINE / type: ligand / ID: 4 / Number of copies: 2 / Formula: GLY
Molecular weightTheoretical: 75.067 Da
Chemical component information

ChemComp-GLY:
GLYCINE / Glycine

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Macromolecule #5: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 5 / Number of copies: 10 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

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Macromolecule #6: GLUTAMIC ACID

MacromoleculeName: GLUTAMIC ACID / type: ligand / ID: 6 / Number of copies: 2 / Formula: GLU
Molecular weightTheoretical: 147.129 Da
Chemical component information

ChemComp-GLU:
GLUTAMIC ACID / 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

Concentration4.0 mg/mL
BufferpH: 8
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 60 sec. / Pretreatment - Atmosphere: AIR / Pretreatment - Pressure: 101.325 kPa
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 281 K / Instrument: FEI VITROBOT MARK IV / Details: Blot for 3 seconds before plunging.
DetailsThis sample was monodisperse

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2.5 µm / Nominal defocus min: 1.5 µm
Image recordingFilm or detector model: DIRECT ELECTRON DE-10 (5k x 4k) / Detector mode: SUPER-RESOLUTION / Digitization - Frames/image: 1-40 / Number grids imaged: 1 / Number real images: 3840 / Average electron dose: 60.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 505204
Startup modelType of model: OTHER
Initial angle assignmentType: OTHER / Software: (Name: RELION (ver. 3.1.1), cryoSPARC)
Final 3D classificationNumber classes: 4 / Software - Name: cryoSPARC
Final angle assignmentType: OTHER / Software - Name: cryoSPARC
Final reconstructionNumber classes used: 2 / Applied symmetry - Point group: C2 (2 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 3.9 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 232194
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

6wi1


Chain - Source name: PDB / Chain - Initial model type: experimental model
RefinementSpace: REAL / Protocol: FLEXIBLE FIT / Overall B value: 220 / Target criteria: Correlation coefficient
Output model

PDB-7yfl:
Structure of GluN1a-GluN2D NMDA receptor in complex with agonists glycine and glutamate.

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