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- EMDB-31309: Structure of the human GluN1-GluN2B NMDA receptor in complex with... -

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Basic information

Entry
Database: EMDB / ID: EMD-31309
TitleStructure of the human GluN1-GluN2B NMDA receptor in complex with S-ketamine,glycine and glutamate
Map data
Sample
  • Complex: tetrameric complex of GluN1 and GluN2B subunits
    • Protein or peptide: Glutamate receptor ionotropic, NMDA 1
    • Protein or peptide: Glutamate receptor ionotropic, NMDA 2B
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: (2~{S})-2-(2-chlorophenyl)-2-(methylamino)cyclohexan-1-one
KeywordsNMDA receptor / ketamine / enantiomer / rapid antidepressant / cryo-EM structure / MEMBRANE PROTEIN
Function / homology
Function and homology information


glycine-gated cation channel activity / excitatory chemical synaptic transmission / Activated NTRK2 signals through FYN / Synaptic adhesion-like molecules / response to glycine / propylene metabolic process / negative regulation of dendritic spine maintenance / Assembly and cell surface presentation of NMDA receptors / regulation of monoatomic cation transmembrane transport / NMDA glutamate receptor activity ...glycine-gated cation channel activity / excitatory chemical synaptic transmission / Activated NTRK2 signals through FYN / Synaptic adhesion-like molecules / response to glycine / propylene metabolic process / negative regulation of dendritic spine maintenance / Assembly and cell surface presentation of NMDA receptors / regulation of monoatomic cation transmembrane transport / NMDA glutamate receptor activity / NMDA selective glutamate receptor complex / Neurexins and neuroligins / glutamate binding / ligand-gated sodium channel activity / neurotransmitter receptor complex / glutamate receptor signaling pathway / calcium ion transmembrane import into cytosol / protein heterotetramerization / glycine binding / monoatomic cation transmembrane transport / positive regulation of reactive oxygen species biosynthetic process / Negative regulation of NMDA receptor-mediated neuronal transmission / Unblocking of NMDA receptors, glutamate binding and activation / positive regulation of calcium ion transport into cytosol / Long-term potentiation / excitatory synapse / monoatomic cation transport / regulation of neuronal synaptic plasticity / monoatomic ion channel complex / positive regulation of excitatory postsynaptic potential / synaptic cleft / positive regulation of synaptic transmission, glutamatergic / calcium ion homeostasis / MECP2 regulates neuronal receptors and channels / glutamate-gated calcium ion channel activity / EPHB-mediated forward signaling / ligand-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential / ionotropic glutamate receptor signaling pathway / sodium ion transmembrane transport / Ras activation upon Ca2+ influx through NMDA receptor / synaptic membrane / regulation of membrane potential / excitatory postsynaptic potential / transmitter-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential / synaptic transmission, glutamatergic / postsynaptic density membrane / brain development / regulation of synaptic plasticity / visual learning / calcium ion transmembrane transport / long-term synaptic potentiation / terminal bouton / synaptic vesicle / late endosome / signaling receptor activity / amyloid-beta binding / RAF/MAP kinase cascade / response to ethanol / chemical synaptic transmission / dendritic spine / postsynaptic membrane / learning or memory / cytoskeleton / calmodulin binding / lysosome / neuron projection / postsynaptic density / calcium ion binding / synapse / dendrite / endoplasmic reticulum membrane / protein-containing complex binding / 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 2B
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 4.07 Å
AuthorsZhang T / Zhang Y / Zhu S
Funding support China, 9 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)31771115 China
Chinese Academy of SciencesXDBS01020000 China
National Natural Science Foundation of China (NSFC)81625022 China
National Natural Science Foundation of China (NSFC)91853205 China
National Natural Science Foundation of China (NSFC)81821005 China
National Key R&D Program of China2017YFA0505700 China
Shanghai Municipal Health Commission in China18431907100 China
Shanghai Municipal Health Commission in China19XD1404700 China
Shanghai Municipal Science and Technology Major Project2018SHZDZX05 China
CitationJournal: Nature / Year: 2021
Title: Structural basis of ketamine action on human NMDA receptors.
Authors: Youyi Zhang / Fei Ye / Tongtong Zhang / Shiyun Lv / Liping Zhou / Daohai Du / He Lin / Fei Guo / Cheng Luo / Shujia Zhu /
Abstract: Ketamine is a non-competitive channel blocker of N-methyl-D-aspartate (NMDA) receptors. A single sub-anaesthetic dose of ketamine produces rapid (within hours) and long-lasting antidepressant effects ...Ketamine is a non-competitive channel blocker of N-methyl-D-aspartate (NMDA) receptors. A single sub-anaesthetic dose of ketamine produces rapid (within hours) and long-lasting antidepressant effects in patients who are resistant to other antidepressants. Ketamine is a racemic mixture of S- and R-ketamine enantiomers, with S-ketamine isomer being the more active antidepressant. Here we describe the cryo-electron microscope structures of human GluN1-GluN2A and GluN1-GluN2B NMDA receptors in complex with S-ketamine, glycine and glutamate. Both electron density maps uncovered the binding pocket for S-ketamine in the central vestibule between the channel gate and selectivity filter. Molecular dynamics simulation showed that S-ketamine moves between two distinct locations within the binding pocket. Two amino acids-leucine 642 on GluN2A (homologous to leucine 643 on GluN2B) and asparagine 616 on GluN1-were identified as key residues that form hydrophobic and hydrogen-bond interactions with ketamine, and mutations at these residues reduced the potency of ketamine in blocking NMDA receptor channel activity. These findings show structurally how ketamine binds to and acts on human NMDA receptors, and pave the way for the future development of ketamine-based antidepressants.
History
DepositionMay 16, 2021-
Header (metadata) releaseJul 28, 2021-
Map releaseJul 28, 2021-
UpdateNov 6, 2024-
Current statusNov 6, 2024Processing site: PDBj / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.01
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.01
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7eu8
  • Surface level: 0.01
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_31309.png

Downloads & links

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Map

FileDownload / File: emd_31309.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.86 Å/pix.
x 300 pix.
= 256.8 Å		0.86 Å/pix.
x 300 pix.
= 256.8 Å		0.86 Å/pix.
x 300 pix.
= 256.8 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.856 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.01 / Movie #1: 0.01
Minimum - Maximum-0.020148966 - 0.053309247
Average (Standard dev.)0.00035601266 (±0.001984706)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions300300300
Spacing300300300
CellA=B=C: 256.8 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.8560.8560.856
M x/y/z300300300
origin x/y/z0.0000.0000.000
length x/y/z256.800256.800256.800
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ400400400
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS300300300
D min/max/mean-0.0200.0530.000

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Supplemental data

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Sample components

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Entire : tetrameric complex of GluN1 and GluN2B subunits

EntireName: tetrameric complex of GluN1 and GluN2B subunits
Components
  • Complex: tetrameric complex of GluN1 and GluN2B subunits
    • Protein or peptide: Glutamate receptor ionotropic, NMDA 1
    • Protein or peptide: Glutamate receptor ionotropic, NMDA 2B
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: (2~{S})-2-(2-chlorophenyl)-2-(methylamino)cyclohexan-1-one

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Supramolecule #1: tetrameric complex of GluN1 and GluN2B subunits

SupramoleculeName: tetrameric complex of GluN1 and GluN2B subunits / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 383.22 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 2B

MacromoleculeName: Glutamate receptor ionotropic, NMDA 2B / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 96.575508 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MKPRAECCSP KFWLVLAVLA VSGSRARSQK SPPSIGIAVI LVGTSDEVAI KDAHEKDDFH HLSVVPRVEL VAMNETDPKS IITRICDLM SDRKIQGVVF ADDTDQEAIA QILDFISAQT LTPILGIHGG SSMIMADKDE SSMFFQFGPS IEQQASVMLN I MEEYDWYI ...String:
MKPRAECCSP KFWLVLAVLA VSGSRARSQK SPPSIGIAVI LVGTSDEVAI KDAHEKDDFH HLSVVPRVEL VAMNETDPKS IITRICDLM SDRKIQGVVF ADDTDQEAIA QILDFISAQT LTPILGIHGG SSMIMADKDE SSMFFQFGPS IEQQASVMLN I MEEYDWYI FSIVTTYFPG YQDFVNKIRS TIENSFVGWE LEEVLLLDMS LDDGDSKIQN QLKKLQSPII LLYCTKEEAT YI FEVANSV GLTGYGYTWI VPSLVAGDTD TVPAEFPTGL ISVSYDEWDY GLPARVRDGI AIITTAASDM LSEHSFIPEP KSS CYNTHE KRIYQSNMLN RYLINVTFEG RNLSFSEDGY QMHPKLVIIL LNKERKWERV GKWKDKSLQM KYYVWPRMCP ETEE QEDDH LSIVTLEEAP FVIVESVDPL SGTCMRNTVP CQKRIVTENK TDEEPGYIKK CCKGFCIDIL KKISKSVKFT YDLYL VTNG KHGKKINGTW NGMIGEVVMK RAYMAVGSLT INEERSEVVD FSVPFIETGI SVMVSRSNGT VSPSAFLEPF SADVWV MMF VMLLIVSAVA VFVFEYFSPV GYNRCLADGR EPGGPSFTIG KAIWLLWGLV FNNSVPVQNP KGTTSKIMVS VWAFFAV IF LASYTANLAA FMIQEEYVDQ VSGLSDKKFQ RPNDFSPPFR FGTVPNGSTE RNIRNNYAEM HAYMGKFNQR GVDDALLS L KTGKLDAFIY DAAVLNYMAG RDEGCKLVTI GSGKVFASTG YGIAIQKDSG WKRQVDLAIL QLFGDGEMEE LEALWLTGI CHNEKNEVMS SQLDIDNMAG VFYMLGAAMA LSLITFICEH LFLEVLFQGP AAAAWSHPQF EK

UniProtKB: Glutamate receptor ionotropic, NMDA 2B

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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: 7 / 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: (2~{S})-2-(2-chlorophenyl)-2-(methylamino)cyclohexan-1-one

MacromoleculeName: (2~{S})-2-(2-chlorophenyl)-2-(methylamino)cyclohexan-1-one
type: ligand / ID: 4 / Number of copies: 1 / Formula: JC9
Molecular weightTheoretical: 237.725 Da
Chemical component information

ChemComp-JC9:
(2~{S})-2-(2-chlorophenyl)-2-(methylamino)cyclohexan-1-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
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
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: OTHER / Imaging mode: BRIGHT FIELD
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: PDB ENTRY
Final reconstructionResolution.type: BY AUTHOR / Resolution: 4.07 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 159306
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION

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Atomic model buiding 1

RefinementSpace: REAL / Protocol: RIGID BODY FIT
Output model

PDB-7eu8:
Structure of the human GluN1-GluN2B NMDA receptor in complex with S-ketamine,glycine and glutamate

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