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Yorodumi- EMDB-31309: Structure of the human GluN1-GluN2B NMDA receptor in complex with... -
+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-31309 | ||||||||||||||||||||||||||||||
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Title | Structure of the human GluN1-GluN2B NMDA receptor in complex with S-ketamine,glycine and glutamate | ||||||||||||||||||||||||||||||
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Sample |
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Function / homology | Function and homology information excitatory chemical synaptic transmission / Activated NTRK2 signals through FYN / Synaptic adhesion-like molecules / propylene metabolic process / response to glycine / positive regulation of cysteine-type endopeptidase activity / negative regulation of dendritic spine maintenance / regulation of monoatomic cation transmembrane transport / glutamate receptor signaling pathway / Assembly and cell surface presentation of NMDA receptors ...excitatory chemical synaptic transmission / Activated NTRK2 signals through FYN / Synaptic adhesion-like molecules / propylene metabolic process / response to glycine / positive regulation of cysteine-type endopeptidase activity / negative regulation of dendritic spine maintenance / 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 / Negative regulation of NMDA receptor-mediated neuronal transmission / 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 / ligand-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential / EPHB-mediated forward signaling / ionotropic glutamate receptor signaling pathway / Ras activation upon Ca2+ influx through NMDA receptor / excitatory postsynaptic potential / positive regulation of synaptic transmission, glutamatergic / 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 / visual learning / regulation of synaptic plasticity / brain development / terminal bouton / late endosome / synaptic vesicle / 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 / lysosome / cytoskeleton / calmodulin binding / neuron projection / 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 | ||||||||||||||||||||||||||||||
Biological species | Homo sapiens (human) | ||||||||||||||||||||||||||||||
Method | single particle reconstruction / cryo EM / Resolution: 4.07 Å | ||||||||||||||||||||||||||||||
Authors | Zhang T / Zhang Y / Zhu S | ||||||||||||||||||||||||||||||
Funding support | China, 9 items
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Citation | Journal: 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 |
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-Structure visualization
Movie |
Movie viewer |
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Structure viewer | EM map: SurfViewMolmilJmol/JSmol |
Supplemental images |
-Downloads & links
-EMDB archive
Map data | emd_31309.map.gz | 9.2 MB | EMDB map data format | |
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Header (meta data) | emd-31309-v30.xml emd-31309.xml | 15.1 KB 15.1 KB | Display Display | EMDB header |
Images | emd_31309.png | 55.4 KB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-31309 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-31309 | HTTPS FTP |
-Validation report
Summary document | emd_31309_validation.pdf.gz | 345.6 KB | Display | EMDB validaton report |
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Full document | emd_31309_full_validation.pdf.gz | 345.2 KB | Display | |
Data in XML | emd_31309_validation.xml.gz | 6.3 KB | Display | |
Data in CIF | emd_31309_validation.cif.gz | 7.2 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-31309 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-31309 | HTTPS FTP |
-Related structure data
Related structure data | 7eu8MC 7eu7C M: atomic model generated by this map C: citing same article (ref.) |
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Similar structure data |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_31309.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Voxel size | X=Y=Z: 0.856 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
CCP4 map header:
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-Supplemental data
-Sample components
-Entire : tetrameric complex of GluN1 and GluN2B subunits
Entire | Name: tetrameric complex of GluN1 and GluN2B subunits |
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Components |
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-Supramolecule #1: tetrameric complex of GluN1 and GluN2B subunits
Supramolecule | Name: tetrameric complex of GluN1 and GluN2B subunits / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2 |
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Source (natural) | Organism: Homo sapiens (human) |
Recombinant expression | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 383.22 kDa/nm |
-Macromolecule #1: Glutamate receptor ionotropic, NMDA 1
Macromolecule | Name: Glutamate receptor ionotropic, NMDA 1 / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 95.236078 KDa |
Recombinant expression | Organism: Homo sapiens (human) |
Sequence | String: 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 |
-Macromolecule #2: Glutamate receptor ionotropic, NMDA 2B
Macromolecule | Name: Glutamate receptor ionotropic, NMDA 2B / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 96.575508 KDa |
Recombinant expression | Organism: Homo sapiens (human) |
Sequence | String: 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 |
-Macromolecule #3: 2-acetamido-2-deoxy-beta-D-glucopyranose
Macromolecule | Name: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 3 / Number of copies: 7 / Formula: NAG |
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Molecular weight | Theoretical: 221.208 Da |
Chemical component information | ChemComp-NAG: |
-Macromolecule #4: (2~{S})-2-(2-chlorophenyl)-2-(methylamino)cyclohexan-1-one
Macromolecule | Name: (2~{S})-2-(2-chlorophenyl)-2-(methylamino)cyclohexan-1-one type: ligand / ID: 4 / Number of copies: 1 / Formula: JC9 |
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Molecular weight | Theoretical: 237.725 Da |
Chemical component information | ChemComp-JC9: |
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Buffer | pH: 8 |
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Vitrification | Cryogen name: ETHANE |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K3 (6k x 4k) / Average electron dose: 60.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: OTHER / Imaging mode: BRIGHT FIELD |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
-Image processing
Final reconstruction | Resolution.type: BY AUTHOR / Resolution: 4.07 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 159306 |
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Initial angle assignment | Type: ANGULAR RECONSTITUTION |
Final angle assignment | Type: ANGULAR RECONSTITUTION |
-Atomic model buiding 1
Refinement | Space: REAL / Protocol: RIGID BODY FIT |
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Output model | PDB-7eu8: |