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- EMDB-27959: D-cycloserine and glutamate bound Human GluN1a-GluN2C NMDA recept... -

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Basic information

Entry
Database: EMDB / ID: EMD-27959
TitleD-cycloserine and glutamate bound Human GluN1a-GluN2C NMDA receptor in nanodisc - intact conformation
Map dataB-factor sharpened map
Sample
  • Complex: Hetero-tetrameric GluN1a-GluN2C NMDA receptors
    • Protein or peptide: Glutamate receptor ionotropic, NMDA 1
    • Protein or peptide: Glutamate receptor ionotropic, NMDA 2C
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
Function / homology
Function and homology information


excitatory chemical synaptic transmission / directional locomotion / Synaptic adhesion-like molecules / protein localization to postsynaptic membrane / propylene metabolic process / response to glycine / glutamate-gated calcium ion channel activity / glutamate receptor signaling pathway / Assembly and cell surface presentation of NMDA receptors / regulation of monoatomic cation transmembrane transport ...excitatory chemical synaptic transmission / directional locomotion / Synaptic adhesion-like molecules / protein localization to postsynaptic membrane / propylene metabolic process / response to glycine / glutamate-gated calcium ion channel activity / glutamate receptor signaling pathway / Assembly and cell surface presentation of NMDA receptors / regulation of monoatomic cation transmembrane transport / 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 / regulation of neuronal synaptic plasticity / Negative regulation of NMDA receptor-mediated neuronal transmission / Unblocking of NMDA receptors, glutamate binding and activation / monoatomic cation transmembrane transport / ligand-gated monoatomic ion channel activity / positive regulation of excitatory postsynaptic potential / Long-term potentiation / neuromuscular process controlling balance / monoatomic cation transport / excitatory synapse / calcium ion homeostasis / synaptic cleft / EPHB-mediated forward signaling / excitatory postsynaptic potential / regulation of membrane potential / 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 / synaptic membrane / synaptic transmission, glutamatergic / long-term synaptic potentiation / postsynaptic density membrane / brain development / regulation of synaptic plasticity / visual learning / negative regulation of protein catabolic process / terminal bouton / response to wounding / 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 / glutamatergic synapse / 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
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 2C
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.75 Å
AuthorsChou T-H / Furukawa H
Funding support United States, 2 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)NS111745 United States
National Institutes of Health/National Institute of Mental Health (NIH/NIMH)MH085926 United States
CitationJournal: Mol Cell / Year: 2022
Title: Structural insights into assembly and function of GluN1-2C, GluN1-2A-2C, and GluN1-2D NMDARs.
Authors: Tsung-Han Chou / Hyunook Kang / Noriko Simorowski / Stephen F Traynelis / Hiro Furukawa /
Abstract: Neurotransmission mediated by diverse subtypes of N-methyl-D-aspartate receptors (NMDARs) is fundamental for basic brain functions and development as well as neuropsychiatric diseases and disorders. ...Neurotransmission mediated by diverse subtypes of N-methyl-D-aspartate receptors (NMDARs) is fundamental for basic brain functions and development as well as neuropsychiatric diseases and disorders. NMDARs are glycine- and glutamate-gated ion channels that exist as heterotetramers composed of obligatory GluN1 and GluN2(A-D) and/or GluN3(A-B). The GluN2C and GluN2D subunits form ion channels with distinct properties and spatio-temporal expression patterns. Here, we provide the structures of the agonist-bound human GluN1-2C NMDAR in the presence and absence of the GluN2C-selective positive allosteric potentiator (PAM), PYD-106, the agonist-bound GluN1-2A-2C tri-heteromeric NMDAR, and agonist-bound GluN1-2D NMDARs by single-particle electron cryomicroscopy. Our analysis shows unique inter-subunit and domain arrangements of the GluN2C NMDARs, which contribute to functional regulation and formation of the PAM binding pocket and is distinct from GluN2D NMDARs. Our findings here provide the fundamental blueprint to study GluN2C- and GluN2D-containing NMDARs, which are uniquely involved in neuropsychiatric disorders.
History
DepositionAug 26, 2022-
Header (metadata) releaseDec 7, 2022-
Map releaseDec 7, 2022-
UpdateDec 14, 2022-
Current statusDec 14, 2022Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_27959.png

Downloads & links

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Map

FileDownload / File: emd_27959.map.gz / Format: CCP4 / Size: 244.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationB-factor sharpened map
Voxel sizeX=Y=Z: 0.856 Å
Density
Contour LevelBy AUTHOR: 0.452
Minimum - Maximum-2.959911 - 5.424305
Average (Standard dev.)-0.0020290206 (±0.09739742)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions400400400
Spacing400400400
CellA=B=C: 342.4 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Half map 1

Fileemd_27959_half_map_1.map
AnnotationHalf map 1
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map 2

Fileemd_27959_half_map_2.map
AnnotationHalf map 2
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Hetero-tetrameric GluN1a-GluN2C NMDA receptors

EntireName: Hetero-tetrameric GluN1a-GluN2C NMDA receptors
Components
  • Complex: Hetero-tetrameric GluN1a-GluN2C NMDA receptors
    • Protein or peptide: Glutamate receptor ionotropic, NMDA 1
    • Protein or peptide: Glutamate receptor ionotropic, NMDA 2C
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: Hetero-tetrameric GluN1a-GluN2C NMDA receptors

SupramoleculeName: Hetero-tetrameric GluN1a-GluN2C NMDA receptors / type: complex / Chimera: Yes / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

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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: 95.081688 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MSTMHLLTFA LLFSCSFARA ASDPKIVNIG AVLSTRKHEQ MFREAVNQAN KRHGSWKIQL NATSVTHKPN AIQMALSVCE DLISSQVYA ILVSHPPTPN DHFTPTPVSY TAGFYRIPVL GLTTRMSIYS DKSIHLSFLR TVPPYSHQSS VWFEMMRVYS W NHIILLVS ...String:
MSTMHLLTFA LLFSCSFARA ASDPKIVNIG 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 KDANGAQ

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Macromolecule #2: Glutamate receptor ionotropic, NMDA 2C

MacromoleculeName: Glutamate receptor ionotropic, NMDA 2C / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 96.958406 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MGTMRLFLLA VLFLFSFARA TGWSHPQFEK GGGSGGGSGG SAWSHPQFEK GALVPRGEQG MTVAVVFSSS GPPQAQFRAR LTPQSFLDL PLEIQPLTVG VNTTNPSSLL TQICGLLGAA HVHGIVFEDN VDTEAVAQIL DFISSQTHVP ILSISGGSAV V LTPKEPGS ...String:
MGTMRLFLLA VLFLFSFARA TGWSHPQFEK GGGSGGGSGG SAWSHPQFEK GALVPRGEQG MTVAVVFSSS GPPQAQFRAR LTPQSFLDL PLEIQPLTVG VNTTNPSSLL TQICGLLGAA HVHGIVFEDN VDTEAVAQIL DFISSQTHVP ILSISGGSAV V LTPKEPGS AFLQLGVSLE QQLQVLFKVL EEYDWSAFAV ITSLHPGHAL FLEGVRAVAD ASHVSWRLLD VVTLELGPGG PR ARTQRLL RQLDAPVFVA YCSREEAEVL FAEAAQAGLV GPGHVWLVPN LALGSTDAPP ATFPVGLISV VTESWRLSLR QKV RDGVAI LALGAHSYWR QHGTLPAPAG DCRVHPGPVS PAREAFYRHL LNVTWEGRDF SFSPGGYLVQ PTMVVIALNR HRLW EMVGR WEHGVLYMKY PVWPRYSASL QPVVDSRHLT VATLEERPFV IVESPDPGTG GCVPNTVPCR RQSNHTFSSG DVAPY TKLC CKGFCIDILK KLARVVKFSY DLYLVTNGKH GKRVRGVWNG MIGEVYYKRA DMAIGSLTIN EERSEIVDFS VPFVET GIS VMVARSNGTV SPSAFLEPYS PAVWVMMFVM CLTVVAITVF MFEYFSPVSY NQNLTRGKKS GGPAFTIGKS VWLLWAL VF NNSVPIENPR GTTSKIMVLV WAFFAVIFLA SYTANLAAFM IQEQYIDTVS GLSDKKFQRP QDQYPPFRFG TVPNGSTE R NIRSNYRDMH THMVKFNQRS VEDALTSLKM GKLDAFIYDA AVLNYMAGKD EGCKLVTIGS GKVFATTGYG IAMQKDSHW KRAIDLALLQ FLGDGETQKL ETVWLSGICQ NEKNEVMSSK LDIDNMAGVF YMLLVAMGLA LLVFAWEHLV YWKLRHSVPN

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Macromolecule #4: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 4 / Number of copies: 9 / 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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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: 7.5
VitrificationCryogen name: ETHANE / Chamber humidity: 85 % / Chamber temperature: 285 K / Instrument: FEI VITROBOT MARK IV

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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: 2.8000000000000003 µm / Nominal defocus min: 1.4000000000000001 µm
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 57.6 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: EMDB MAP
EMDB ID:

21674

Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.75 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 3.3.2) / Number images used: 130917

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