[English] 日本語
Yorodumi- EMDB-24946: Glycine and glutamate bound GluN1a-GluN2B NMDA receptors in non-a... -
+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-24946 | |||||||||
---|---|---|---|---|---|---|---|---|---|---|
Title | Glycine and glutamate bound GluN1a-GluN2B NMDA receptors in non-active 1 conformation at 2.97 Angstrom resolution | |||||||||
Map data | B-factor sharpened map | |||||||||
Sample |
| |||||||||
Function / homology | Function and homology information neurotransmitter receptor activity involved in regulation of postsynaptic membrane potential / cellular response to curcumin / cellular response to corticosterone stimulus / cellular response to magnesium starvation / regulation of postsynaptic cytosolic calcium ion concentration / sensory organ development / sensitization / pons maturation / regulation of cell communication / positive regulation of Schwann cell migration ...neurotransmitter receptor activity involved in regulation of postsynaptic membrane potential / cellular response to curcumin / cellular response to corticosterone stimulus / cellular response to magnesium starvation / regulation of postsynaptic cytosolic calcium ion concentration / sensory organ development / sensitization / pons maturation / regulation of cell communication / positive regulation of Schwann cell migration / EPHB-mediated forward signaling / neurotransmitter receptor activity involved in regulation of postsynaptic cytosolic calcium ion concentration / response to hydrogen sulfide / Assembly and cell surface presentation of NMDA receptors / olfactory learning / regulation of protein kinase A signaling / conditioned taste aversion / dendritic branch / response to other organism / regulation of respiratory gaseous exchange / protein localization to postsynaptic membrane / positive regulation of inhibitory postsynaptic potential / apical dendrite / propylene metabolic process / response to glycine / regulation of ARF protein signal transduction / fear response / response to methylmercury / positive regulation of cysteine-type endopeptidase activity / voltage-gated monoatomic cation channel activity / cellular response to dsRNA / response to carbohydrate / negative regulation of dendritic spine maintenance / regulation of monoatomic cation transmembrane transport / interleukin-1 receptor binding / cellular response to lipid / response to morphine / NMDA glutamate receptor activity / positive regulation of glutamate secretion / response to growth hormone / Synaptic adhesion-like molecules / NMDA selective glutamate receptor complex / RAF/MAP kinase cascade / parallel fiber to Purkinje cell synapse / NMDA selective glutamate receptor signaling pathway / response to manganese ion / calcium ion transmembrane import into cytosol / glutamate binding / neuromuscular process / positive regulation of reactive oxygen species biosynthetic process / protein heterotetramerization / regulation of synapse assembly / glycine binding / positive regulation of calcium ion transport into cytosol / regulation of dendrite morphogenesis / regulation of axonogenesis / male mating behavior / heterocyclic compound binding / action potential / suckling behavior / behavioral response to pain / startle response / response to amine / receptor clustering / monoatomic cation transmembrane transport / regulation of neuronal synaptic plasticity / monoatomic cation transport / associative learning / positive regulation of excitatory postsynaptic potential / regulation of MAPK cascade / social behavior / response to magnesium ion / ligand-gated monoatomic ion channel activity / cellular response to organic cyclic compound / excitatory synapse / extracellularly glutamate-gated ion channel activity / cellular response to glycine / positive regulation of dendritic spine maintenance / small molecule binding / neuron development / behavioral fear response / regulation of postsynaptic membrane potential / Unblocking of NMDA receptors, glutamate binding and activation / postsynaptic density, intracellular component / phosphatase binding / cellular response to manganese ion / glutamate-gated calcium ion channel activity / calcium ion homeostasis / glutamate receptor binding / D2 dopamine receptor binding / multicellular organismal response to stress / prepulse inhibition / monoatomic cation channel activity / long-term memory / detection of mechanical stimulus involved in sensory perception of pain / regulation of neuron apoptotic process / response to electrical stimulus / synaptic cleft / response to mechanical stimulus / glutamate-gated receptor activity Similarity search - Function | |||||||||
Biological species | Rattus norvegicus (Norway rat) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 2.97 Å | |||||||||
Authors | Chou T-H / Furukawa H | |||||||||
Funding support | United States, 2 items
| |||||||||
Citation | Journal: Nat Struct Mol Biol / Year: 2022 Title: Structural insights into binding of therapeutic channel blockers in NMDA receptors. Authors: Tsung-Han Chou / Max Epstein / Kevin Michalski / Eve Fine / Philip C Biggin / Hiro Furukawa / Abstract: Excitatory signaling mediated by N-methyl-D-aspartate receptor (NMDAR) is critical for brain development and function, as well as for neurological diseases and disorders. Channel blockers of NMDARs ...Excitatory signaling mediated by N-methyl-D-aspartate receptor (NMDAR) is critical for brain development and function, as well as for neurological diseases and disorders. Channel blockers of NMDARs are of medical interest owing to their potential for treating depression, Alzheimer's disease, and epilepsy. However, precise mechanisms underlying binding and channel blockade have remained limited owing to challenges in obtaining high-resolution structures at the binding site within the transmembrane domains. Here, we monitor the binding of three clinically important channel blockers: phencyclidine, ketamine, and memantine in GluN1-2B NMDARs at local resolutions of 2.5-3.5 Å around the binding site using single-particle electron cryo-microscopy, molecular dynamics simulations, and electrophysiology. The channel blockers form different extents of interactions with the pore-lining residues, which control mostly off-speeds but not on-speeds. Our comparative analyses of the three unique NMDAR channel blockers provide a blueprint for developing therapeutic compounds with minimal side effects. | |||||||||
History |
|
-Structure visualization
Supplemental images |
---|
-Downloads & links
-EMDB archive
Map data | emd_24946.map.gz | 226.9 MB | EMDB map data format | |
---|---|---|---|---|
Header (meta data) | emd-24946-v30.xml emd-24946.xml | 14.4 KB 14.4 KB | Display Display | EMDB header |
Images | emd_24946.png | 41.1 KB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-24946 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-24946 | HTTPS FTP |
-Validation report
Summary document | emd_24946_validation.pdf.gz | 527.6 KB | Display | EMDB validaton report |
---|---|---|---|---|
Full document | emd_24946_full_validation.pdf.gz | 527.2 KB | Display | |
Data in XML | emd_24946_validation.xml.gz | 7.4 KB | Display | |
Data in CIF | emd_24946_validation.cif.gz | 8.4 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-24946 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-24946 | HTTPS FTP |
-Related structure data
Related structure data | 7saaMC 7sabC 7sacC 7sadC C: citing same article (ref.) M: atomic model generated by this map |
---|---|
Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
---|---|
Related items in Molecule of the Month |
-Map
File | Download / File: emd_24946.map.gz / Format: CCP4 / Size: 244.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Annotation | B-factor sharpened map | ||||||||||||||||||||
Voxel size | X=Y=Z: 0.856 Å | ||||||||||||||||||||
Density |
| ||||||||||||||||||||
Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
|
-Supplemental data
-Sample components
-Entire : Hetero-tetrameric GluN1a-GluN2B NMDA receptors
Entire | Name: Hetero-tetrameric GluN1a-GluN2B NMDA receptors |
---|---|
Components |
|
-Supramolecule #1: Hetero-tetrameric GluN1a-GluN2B NMDA receptors
Supramolecule | Name: Hetero-tetrameric GluN1a-GluN2B NMDA receptors / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2 |
---|---|
Source (natural) | Organism: Rattus norvegicus (Norway rat) |
Recombinant expression | Organism: Spodoptera frugiperda (fall armyworm) |
-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 |
---|---|
Source (natural) | Organism: Rattus norvegicus (Norway rat) |
Molecular weight | Theoretical: 95.225883 KDa |
Recombinant expression | Organism: Spodoptera frugiperda (fall armyworm) |
Sequence | String: MSTMHLLTFA LLFSCSFARA ASDPKIVNIG AVLSTRKHEQ MFREAVNQAN KRHGSWKIQL QATSVTHKPN AIQMALSVCE DLISSQVYA ILVSHPPTPN DHFTPTPVSY TAGFYRIPVL GLTTRMSIYS DKSIHLSFLR TVPPYSHQSS VWFEMMRVYN W NHIILLVS ...String: MSTMHLLTFA LLFSCSFARA ASDPKIVNIG AVLSTRKHEQ MFREAVNQAN KRHGSWKIQL QATSVTHKPN AIQMALSVCE DLISSQVYA ILVSHPPTPN DHFTPTPVSY TAGFYRIPVL GLTTRMSIYS DKSIHLSFLR TVPPYSHQSS VWFEMMRVYN W NHIILLVS DDHEGRAAQK RLETLLEERE SKAEKVLQFD PGTKNVTALL MEARELEARV IILSASEDDA ATVYRAAAML DM TGSGYVW LVGEREISGN ALRYAPDGII GLQLINGKNE SAHISDAVGV VAQAVHELLE KENITDPPRG CVGNTNIWKT GPL FKRVLM SSKYADGVTG RVEFNEDGDR KFAQYSIMNL QNRKLVQVGI YNGTHVIPND RKIIWPGGET EKPRGYQMST RLKI VTIHQ EPFVYVKPTM SDGTCKEEFT VNGDPVKKVI CTGPNDTSPG SPRHTVPQCC YGFCIDLLIK LARTMQFTYE VHLVA DGKF GTQERVQNSN 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 MRKDSPWKQQ VSLSILKSHE NGFMEDLDKT WVRYQECDS RSNAPATLTF ENMAGVFMLV AGGIVAGIFL IFIEIAYKRH KDANGAQ |
-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 |
---|---|
Source (natural) | Organism: Rattus norvegicus (Norway rat) |
Molecular weight | Theoretical: 98.888945 KDa |
Recombinant expression | Organism: Spodoptera frugiperda (fall armyworm) |
Sequence | String: MGTMRLFLLA VLFLFSFARA TGWSHPQFEK GGGSGGGSGG SAWSHPQFEK GALVPRGRSQ KSPPSIGIAV ILVGTSDEVA IKDAHEKDD FHHLSVVPRV ELVAMNETDP KSIITRICDL MSDRKIQGVV FADDTDQEAI AQILDFISAQ TLTPILGIHG G SSMIMADK ...String: MGTMRLFLLA VLFLFSFARA TGWSHPQFEK GGGSGGGSGG SAWSHPQFEK GALVPRGRSQ KSPPSIGIAV ILVGTSDEVA IKDAHEKDD FHHLSVVPRV ELVAMNETDP KSIITRICDL MSDRKIQGVV FADDTDQEAI AQILDFISAQ TLTPILGIHG G SSMIMADK DESSMFFQFG PSIEQQASVM LNIMEEYDWY IFSIVTTYFP GYQDFVNKIR STIENSFVGW ELEEVLLLDM SL DDGDSKI QNQLKKLQSP IILLYCTKEE ATYIFEVANS VGLTGYGYTW IVPSLVAGDT DTVPSEFPTG LISVSYDEWD YGL PARVRD GIAIITTAAS DMLSEHSFIP EPKSSCYNTH EKRIYQSNML NRYLINVTFE GRNLSFSEDG YQMHPKLVII LLNK ERKWE RVGKWKDKSL QMKYYVWPRM CPETEEQEDD HLSIVTLEEA PFVIVESVDP LSGTCMRNTV PCQKRIISEN KTDEE PGYI KKCCKGFCID ILKKISKSVK FTYDLYLVTN GKHGKKINGT WNGMIGEVVM KRAYMAVGSL TINEERSEVV DFSVPF IET GISVMVSRSN GTVSPSAFLE PFSADVWVMM FVMLLIVSAV AVFVFEYFSP VGYNRCLADG REPGGPSFTI GKAIWLL WG LVFNNSVPVQ NPKGTTSKIM VSVWAFFAVI FLASYTANLA AFMIQEEYVD QVSGLSDKKF QRPNDFSPPF RFGTVPNG S TERNIRNNYA EMHAYMGKFN QRGVDDALLS LKTGKLDAFI YDAAVLNYMA GRDEGCKLVT IGSGKVFAST GYGIAIQKD SGWKRQVDLA ILQLFGDGEM EELEALWLTG ICHNEKNEVM SSQLDIDNMA GVFYMLGAAM ALSLITFICE HLFYWQFRHS FMG |
-Macromolecule #4: 2-acetamido-2-deoxy-beta-D-glucopyranose
Macromolecule | Name: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 4 / Number of copies: 8 / Formula: NAG |
---|---|
Molecular weight | Theoretical: 221.208 Da |
Chemical component information | ChemComp-NAG: |
-Macromolecule #5: GLYCINE
Macromolecule | Name: GLYCINE / type: ligand / ID: 5 / Number of copies: 2 / Formula: GLY |
---|---|
Molecular weight | Theoretical: 75.067 Da |
Chemical component information | ChemComp-GLY: |
-Macromolecule #6: GLUTAMIC ACID
Macromolecule | Name: GLUTAMIC ACID / type: ligand / ID: 6 / Number of copies: 2 / Formula: GLU |
---|---|
Molecular weight | Theoretical: 147.129 Da |
Chemical component information | ChemComp-GLU: |
-Experimental details
-Structure determination
Method | cryo EM |
---|---|
Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Concentration | 4 mg/mL |
---|---|
Buffer | pH: 7.5 |
Grid | Model: UltrAuFoil R1.2/1.3 / Material: GOLD / Pretreatment - Type: GLOW DISCHARGE |
Vitrification | Cryogen name: ETHANE / Chamber humidity: 85 % / Chamber temperature: 285 K / Instrument: FEI VITROBOT MARK IV |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
---|---|
Image recording | Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 57.6 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
-Image processing
Final reconstruction | Resolution.type: BY AUTHOR / Resolution: 2.97 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cisTEM (ver. 1.0.2) / Number images used: 378892 |
---|---|
Initial angle assignment | Type: MAXIMUM LIKELIHOOD |
Final angle assignment | Type: MAXIMUM LIKELIHOOD |