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- EMDB-24948: S-(+)-ketamine bound GluN1a-GluN2B NMDA receptors at 3.69 Angstro... -

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Basic information

Entry
Database: EMDB / ID: EMD-24948
TitleS-(+)-ketamine bound GluN1a-GluN2B NMDA receptors at 3.69 Angstrom resolution
Map dataB-factor sharpened map
Sample
  • Complex: Hetero-tetrameric GluN1a-GluN2B NMDA receptors
    • 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: GLYCINE
  • Ligand: GLUTAMIC ACID
  • Ligand: (2~{S})-2-(2-chlorophenyl)-2-(methylamino)cyclohexan-1-one
KeywordsLigand-gated ion channel / ionotropic glutamate receptor / synaptic protein / voltage-gate ion channel / TRANSPORT PROTEIN
Function / homology
Function and homology information


cellular response to curcumin / cellular response to corticosterone stimulus / cellular response to magnesium starvation / sensory organ development / EPHB-mediated forward signaling / pons maturation / regulation of cAMP/PKA signal transduction / Assembly and cell surface presentation of NMDA receptors / response to hydrogen sulfide / regulation of cell communication ...cellular response to curcumin / cellular response to corticosterone stimulus / cellular response to magnesium starvation / sensory organ development / EPHB-mediated forward signaling / pons maturation / regulation of cAMP/PKA signal transduction / Assembly and cell surface presentation of NMDA receptors / response to hydrogen sulfide / regulation of cell communication / auditory behavior / positive regulation of Schwann cell migration / sensitization / olfactory learning / conditioned taste aversion / response to other organism / dendritic branch / fear response / regulation of respiratory gaseous exchange / response to methylmercury / apical dendrite / protein localization to postsynaptic membrane / regulation of ARF protein signal transduction / response to manganese ion / response to carbohydrate / transmitter-gated monoatomic ion channel activity / suckling behavior / positive regulation of inhibitory postsynaptic potential / interleukin-1 receptor binding / cellular response to dsRNA / propylene metabolic process / response to glycine / cellular response to lipid / response to growth hormone / negative regulation of dendritic spine maintenance / RAF/MAP kinase cascade / heterocyclic compound binding / response to amine / positive regulation of glutamate secretion / Synaptic adhesion-like molecules / regulation of monoatomic cation transmembrane transport / NMDA glutamate receptor activity / response to glycoside / NMDA selective glutamate receptor complex / voltage-gated monoatomic cation channel activity / glutamate binding / neurotransmitter receptor complex / ligand-gated sodium channel activity / regulation of axonogenesis / calcium ion transmembrane import into cytosol / neuromuscular process / response to morphine / regulation of dendrite morphogenesis / protein heterotetramerization / male mating behavior / regulation of synapse assembly / glycine binding / small molecule binding / receptor clustering / startle response / positive regulation of reactive oxygen species biosynthetic process / parallel fiber to Purkinje cell synapse / behavioral response to pain / monoatomic cation transmembrane transport / regulation of MAPK cascade / monoatomic ion channel complex / cellular response to glycine / response to magnesium ion / positive regulation of calcium ion transport into cytosol / regulation of postsynaptic membrane potential / response to electrical stimulus / action potential / extracellularly glutamate-gated ion channel activity / associative learning / positive regulation of dendritic spine maintenance / regulation of neuronal synaptic plasticity / monoatomic cation transport / social behavior / Unblocking of NMDA receptors, glutamate binding and activation / glutamate receptor binding / response to mechanical stimulus / prepulse inhibition / detection of mechanical stimulus involved in sensory perception of pain / long-term memory / neuron development / multicellular organismal response to stress / phosphatase binding / positive regulation of synaptic transmission, glutamatergic / postsynaptic density, intracellular component / behavioral fear response / response to fungicide / monoatomic cation channel activity / synaptic cleft / calcium ion homeostasis / glutamate-gated receptor activity / cellular response to manganese ion / regulation of long-term synaptic depression / D2 dopamine receptor binding / response to cytokine / glutamate-gated calcium ion channel activity
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 speciesRattus norvegicus (Norway rat)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.69 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: 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
DepositionSep 22, 2021-
Header (metadata) releaseJul 20, 2022-
Map releaseJul 20, 2022-
UpdateMay 21, 2025-
Current statusMay 21, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_24948.png

Downloads & links

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Map

FileDownload / File: emd_24948.map.gz / Format: CCP4 / Size: 244.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationB-factor sharpened map
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.86 Å/pix.
x 400 pix.
= 342.4 Å		0.86 Å/pix.
x 400 pix.
= 342.4 Å		0.86 Å/pix.
x 400 pix.
= 342.4 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: 1.6
Minimum - Maximum-5.4537334 - 12.535672
Average (Standard dev.)0.0035266317 (±0.35195714)
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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Sample components

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Entire : Hetero-tetrameric GluN1a-GluN2B NMDA receptors

EntireName: Hetero-tetrameric GluN1a-GluN2B NMDA receptors
Components
  • Complex: Hetero-tetrameric GluN1a-GluN2B NMDA receptors
    • 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: GLYCINE
  • Ligand: GLUTAMIC ACID
  • Ligand: (2~{S})-2-(2-chlorophenyl)-2-(methylamino)cyclohexan-1-one

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Supramolecule #1: Hetero-tetrameric GluN1a-GluN2B NMDA receptors

SupramoleculeName: Hetero-tetrameric GluN1a-GluN2B NMDA receptors / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Rattus norvegicus (Norway rat)

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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: Rattus norvegicus (Norway rat)
Molecular weightTheoretical: 95.225883 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: 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

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: Rattus norvegicus (Norway rat)
Molecular weightTheoretical: 98.888945 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: 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

UniProtKB: Glutamate receptor ionotropic, NMDA 2B

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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: 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 #5: GLYCINE

MacromoleculeName: GLYCINE / type: ligand / ID: 5 / Number of copies: 2 / Formula: GLY
Molecular weightTheoretical: 75.067 Da
Chemical component information

ChemComp-GLY:
GLYCINE

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Macromolecule #6: GLUTAMIC ACID

MacromoleculeName: GLUTAMIC ACID / type: ligand / ID: 6 / Number of copies: 2 / Formula: GLU
Molecular weightTheoretical: 147.129 Da
Chemical component information

ChemComp-GLU:
GLUTAMIC ACID

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

MacromoleculeName: (2~{S})-2-(2-chlorophenyl)-2-(methylamino)cyclohexan-1-one
type: ligand / ID: 7 / 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 / antidepressant*YM

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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
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 57.6 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 correctionType: NONE
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.69 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cisTEM (ver. 1.0.2) / Number images used: 434625
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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