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- EMDB-31231: Structure of the human GluN1/GluN2A NMDA receptor in the glycine/... -

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Basic information

Entry
Database: EMDB / ID: EMD-31231
TitleStructure of the human GluN1/GluN2A NMDA receptor in the glycine/glutamate/GNE-6901/9-AA bound state
Map data
Sample
  • Complex: Structure of the human GluN1/GluN2A NMDA receptor in the glycine/glutamate/GNE-6901/9-AA bound state
    • Protein or peptide: Glutamate receptor ionotropic, NMDA 2A
    • Protein or peptide: Glutamate receptor ionotropic, NMDA 1
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: 9-AMINOACRIDINE
  • Ligand: 7-[(4-fluoranylphenoxy)methyl]-3-[(1~{R},2~{R})-2-(hydroxymethyl)cyclopropyl]-2-methyl-[1,3]thiazolo[3,2-a]pyrimidin-5-one
Function / homology
Function and homology information


excitatory chemical synaptic transmission / directional locomotion / Synaptic adhesion-like molecules / serotonin metabolic process / protein localization to postsynaptic membrane / propylene metabolic process / response to glycine / sleep / activation of cysteine-type endopeptidase activity / regulation of monoatomic cation transmembrane transport ...excitatory chemical synaptic transmission / directional locomotion / Synaptic adhesion-like molecules / serotonin metabolic process / protein localization to postsynaptic membrane / propylene metabolic process / response to glycine / sleep / activation of cysteine-type endopeptidase activity / regulation of monoatomic cation transmembrane transport / glutamate receptor signaling pathway / Assembly and cell surface presentation of NMDA receptors / NMDA glutamate receptor activity / Neurexins and neuroligins / NMDA selective glutamate receptor complex / glutamate-gated calcium ion channel activity / 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 / dopamine metabolic process / Negative regulation of NMDA receptor-mediated neuronal transmission / startle response / Unblocking of NMDA receptors, glutamate binding and activation / monoatomic cation transmembrane transport / monoatomic cation transport / regulation of neuronal synaptic plasticity / positive regulation of excitatory postsynaptic potential / ligand-gated monoatomic ion channel activity / Long-term potentiation / excitatory synapse / calcium ion homeostasis / synaptic cleft / MECP2 regulates neuronal receptors and channels / sensory perception of pain / EPHB-mediated forward signaling / response to amphetamine / ionotropic glutamate receptor signaling pathway / Ras activation upon Ca2+ influx through NMDA receptor / excitatory postsynaptic potential / positive regulation of synaptic transmission, glutamatergic / neurogenesis / synaptic membrane / synaptic transmission, glutamatergic / transmitter-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential / regulation of membrane potential / long-term synaptic potentiation / postsynaptic density membrane / protein catabolic process / visual learning / regulation of synaptic plasticity / cytoplasmic vesicle membrane / negative regulation of protein catabolic process / brain development / terminal bouton / memory / response to wounding / synaptic vesicle / presynaptic membrane / signaling receptor activity / amyloid-beta binding / RAF/MAP kinase cascade / chemical synaptic transmission / postsynaptic membrane / response to ethanol / dendritic spine / postsynaptic density / learning or memory / calmodulin binding / response to xenobiotic stimulus / neuron projection / positive regulation of apoptotic process / glutamatergic synapse / synapse / calcium ion binding / dendrite / protein-containing complex binding / endoplasmic reticulum membrane / 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 / : / : / 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 ...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 2A
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 4.3 Å
AuthorsWang H / Zhu S
Funding support China, European Union, 5 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)31771115 China
European Research Council (ERC)693021European Union
National Key R&D Program of China2017YFA0505700 China
Strategic Priority Research Program of Chinese Academy of SciencesXDB32020000 China
Shanghai Municipal Science and Technology Major Project2018SHZDZX05 China
CitationJournal: Neuron / Year: 2021
Title: Gating mechanism and a modulatory niche of human GluN1-GluN2A NMDA receptors.
Authors: Han Wang / Shiyun Lv / David Stroebel / Jinbao Zhang / Yijie Pan / Xuejing Huang / Xing Zhang / Pierre Paoletti / Shujia Zhu /
Abstract: N-methyl-D-aspartate (NMDA) receptors are glutamate-gated calcium-permeable ion channels that are widely implicated in synaptic transmission and plasticity. Here, we report a gallery of cryo-electron ...N-methyl-D-aspartate (NMDA) receptors are glutamate-gated calcium-permeable ion channels that are widely implicated in synaptic transmission and plasticity. Here, we report a gallery of cryo-electron microscopy (cryo-EM) structures of the human GluN1-GluN2A NMDA receptor at an overall resolution of 4 Å in complex with distinct ligands or modulators. In the full-length context of GluN1-GluN2A receptors, we visualize the competitive antagonists bound to the ligand-binding domains (LBDs) of GluN1 and GluN2A subunits, respectively. We reveal that the binding of positive allosteric modulator shortens the distance between LBDs and the transmembrane domain (TMD), which further stretches the opening of the gate. In addition, we unexpectedly visualize the binding cavity of the "foot-in-the-door" blocker 9-aminoacridine within the LBD-TMD linker region, differing from the conventional "trapping" blocker binding site at the vestibule within the TMD. Our study provides molecular insights into the crosstalk between LBDs and TMD during channel activation, inhibition, and allosteric transition.
History
DepositionApr 22, 2021-
Header (metadata) releaseJun 30, 2021-
Map releaseJun 30, 2021-
UpdateAug 18, 2021-
Current statusAug 18, 2021Processing site: PDBj / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.0102
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.0102
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7eou
  • Surface level: 0.0102
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_31231.png

Downloads & links

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Map

FileDownload / File: emd_31231.map.gz / Format: CCP4 / Size: 67 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.08 Å
Density
Contour LevelBy AUTHOR: 0.0102 / Movie #1: 0.0102
Minimum - Maximum-0.01938063 - 0.04292578
Average (Standard dev.)0.00028855476 (±0.0018780825)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions260260260
Spacing260260260
CellA=B=C: 280.80002 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.081.081.08
M x/y/z260260260
origin x/y/z0.0000.0000.000
length x/y/z280.800280.800280.800
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ220220220
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS260260260
D min/max/mean-0.0190.0430.000

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Supplemental data

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Sample components

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Entire : Structure of the human GluN1/GluN2A NMDA receptor in the glycine/...

EntireName: Structure of the human GluN1/GluN2A NMDA receptor in the glycine/glutamate/GNE-6901/9-AA bound state
Components
  • Complex: Structure of the human GluN1/GluN2A NMDA receptor in the glycine/glutamate/GNE-6901/9-AA bound state
    • Protein or peptide: Glutamate receptor ionotropic, NMDA 2A
    • Protein or peptide: Glutamate receptor ionotropic, NMDA 1
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: 9-AMINOACRIDINE
  • Ligand: 7-[(4-fluoranylphenoxy)methyl]-3-[(1~{R},2~{R})-2-(hydroxymethyl)cyclopropyl]-2-methyl-[1,3]thiazolo[3,2-a]pyrimidin-5-one

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Supramolecule #1: Structure of the human GluN1/GluN2A NMDA receptor in the glycine/...

SupramoleculeName: Structure of the human GluN1/GluN2A NMDA receptor in the glycine/glutamate/GNE-6901/9-AA bound state
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Homo sapiens (human) / Recombinant cell: HEK293S

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Macromolecule #1: Glutamate receptor ionotropic, NMDA 2A

MacromoleculeName: Glutamate receptor ionotropic, NMDA 2A / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 95.537703 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 MIQEEFVDQV TGLSDKKFQR PHDYSPPFRF GTVPNGSTER NIRNNYPYMH QYMTKFNQKG VEDALVSL K TGKLDAFIYD AAVLNYKAGR DEGCKLVTIG SGYIFATTGY GIALQKGSPW KRQIDLALLQ FVGDGEMEEL ETCWLTGIC HNEKNEVMSS QLDIDNMAGV FYMLAAAMAL SLITFIWEHL FYKSRAEAKR MKG

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Macromolecule #2: Glutamate receptor ionotropic, NMDA 1

MacromoleculeName: Glutamate receptor ionotropic, NMDA 1 / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 95.210102 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 FRRQVCLSTM YRHMEKHNYE SAAEAIQA V RDNKLHAFIW DSAVLEFEAS QKCDLVTTGE LFFRSGFGIG MRKDSPWKQN VSLSILKSHE NGFMEDLDKT WVRYQECDS RSNAPATLTF ENMAGVFMLV AGGIVAGIFL IFIEIAYKRH KDARRKQ

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Macromolecule #3: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 3 / Number of copies: 16 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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Macromolecule #4: 9-AMINOACRIDINE

MacromoleculeName: 9-AMINOACRIDINE / type: ligand / ID: 4 / Number of copies: 1 / Formula: AA
Molecular weightTheoretical: 195.24 Da
Chemical component information

ChemComp-AA:
9-AMINOACRIDINE

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Macromolecule #5: 7-[(4-fluoranylphenoxy)methyl]-3-[(1~{R},2~{R})-2-(hydroxymethyl)...

MacromoleculeName: 7-[(4-fluoranylphenoxy)methyl]-3-[(1~{R},2~{R})-2-(hydroxymethyl)cyclopropyl]-2-methyl-[1,3]thiazolo[3,2-a]pyrimidin-5-one
type: ligand / ID: 5 / Number of copies: 2 / Formula: 6RM
Molecular weightTheoretical: 360.403 Da
Chemical component information

ChemComp-6RM:
7-[(4-fluoranylphenoxy)methyl]-3-[(1~{R},2~{R})-2-(hydroxymethyl)cyclopropyl]-2-methyl-[1,3]thiazolo[3,2-a]pyrimidin-5-one

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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

BufferpH: 8
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Atmosphere: AIR
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 281 K / Instrument: FEI VITROBOT MARK III

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Specialist opticsPhase plate: OTHER / Energy filter - Name: GIF Bioquantum
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 60.0 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

CTF correctionSoftware - Name: RELION
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

6ira

Final reconstructionApplied symmetry - Point group: C2 (2 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 4.3 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION / Number images used: 80969
Initial angle assignmentType: ANGULAR RECONSTITUTION / Software - Name: RELION
Final angle assignmentType: ANGULAR RECONSTITUTION / Software - Name: RELION

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Atomic model buiding 1

Initial modelPDB ID:

6ira

RefinementSpace: REAL / Protocol: RIGID BODY FIT
Output model

PDB-7eou:
Structure of the human GluN1/GluN2A NMDA receptor in the glycine/glutamate/GNE-6901/9-AA bound state

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