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- EMDB-38847: GluN1b-GluN2D NMDA receptor in complex with competitive antagonis... -

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Basic information

Entry
Database: EMDB / ID: EMD-38847
TitleGluN1b-GluN2D NMDA receptor in complex with competitive antagonist R-CPP and allosteric inhibitor YY-23
Map data
Sample
  • Complex: N-methyl-D-aspartate receptors
    • Protein or peptide: Isoform 6 of Glutamate receptor ionotropic, NMDA 1
    • Protein or peptide: Glutamate receptor ionotropic, NMDA 2D
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: (2~{R},3~{S},4~{S},5~{R},6~{R})-2-(hydroxymethyl)-6-[(2~{S})-2-methyl-4-[(1~{R},2~{R},4~{S},6~{S},7~{S},8~{R},9~{S},12~{S},13~{R},16~{S},18~{R})-7,9,13,18-tetramethyl-16-oxidanyl-5-oxapentacyclo[10.8.0.0^{2,9}.0^{4,8}.0^{13,18}]icosan-6-yl]butoxy]oxane-3,4,5-triol
Keywordsion channel / calcium permeable / glutamate receptor / neuronal expression / MEMBRANE PROTEIN / MEMBRANE PROTEIN-INHIBITOR complex
Function / homology
Function and homology information


glycine-gated cation channel activity / regulation of sensory perception of pain / excitatory chemical synaptic transmission / Synaptic adhesion-like molecules / cellular response to L-glutamate / propylene metabolic process / response to glycine / Assembly and cell surface presentation of NMDA receptors / neurotransmitter receptor complex / regulation of monoatomic cation transmembrane transport ...glycine-gated cation channel activity / regulation of sensory perception of pain / excitatory chemical synaptic transmission / Synaptic adhesion-like molecules / cellular response to L-glutamate / propylene metabolic process / response to glycine / Assembly and cell surface presentation of NMDA receptors / neurotransmitter receptor complex / regulation of monoatomic cation transmembrane transport / Neurexins and neuroligins / NMDA glutamate receptor activity / voltage-gated monoatomic cation channel activity / NMDA selective glutamate receptor complex / glutamate binding / ligand-gated sodium channel activity / calcium ion transmembrane import into cytosol / protein heterotetramerization / glycine binding / startle response / positive regulation of reactive oxygen species biosynthetic process / Negative regulation of NMDA receptor-mediated neuronal transmission / Unblocking of NMDA receptors, glutamate binding and activation / monoatomic cation transmembrane transport / positive regulation of calcium ion transport into cytosol / Long-term potentiation / regulation of neuronal synaptic plasticity / monoatomic cation transport / ligand-gated monoatomic ion channel activity / synaptic cleft / calcium ion homeostasis / positive regulation of synaptic transmission, glutamatergic / glutamate-gated receptor activity / glutamate-gated calcium ion channel activity / EPHB-mediated forward signaling / presynaptic active zone membrane / excitatory synapse / ionotropic glutamate receptor signaling pathway / ligand-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential / Ras activation upon Ca2+ influx through NMDA receptor / positive regulation of excitatory postsynaptic potential / hippocampal mossy fiber to CA3 synapse / sodium ion transmembrane transport / synaptic membrane / adult locomotory behavior / excitatory postsynaptic potential / synaptic transmission, glutamatergic / regulation of membrane potential / transmitter-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential / brain development / regulation of synaptic plasticity / visual learning / postsynaptic density membrane / calcium ion transmembrane transport / terminal bouton / synaptic vesicle / long-term synaptic potentiation / amyloid-beta binding / signaling receptor activity / RAF/MAP kinase cascade / dendritic spine / chemical synaptic transmission / response to ethanol / postsynaptic membrane / calmodulin binding / neuron projection / postsynaptic density / calcium ion binding / synapse / dendrite / endoplasmic reticulum membrane / protein-containing complex binding / glutamatergic synapse / cell surface / positive regulation of transcription by RNA polymerase II / plasma membrane / cytoplasm
Similarity search - Function
: / : / 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. ...: / : / 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 2D / Glutamate receptor ionotropic, NMDA 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 4.2 Å
AuthorsZhang JL / Zhu SJ / Guo F
Funding support China, 9 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)31771115 China
National Natural Science Foundation of China (NSFC)31671049 China
National Natural Science Foundation of China (NSFC)81030065 China
Chinese Academy of SciencesXDB32020000 China
Chinese Academy of SciencesXDA12040214 China
Chinese Academy of SciencesXDA12040220 China
National Natural Science Foundation of China (NSFC)81803828 China
Chinese Academy of Sciences2019280 China
National Natural Science Foundation of China (NSFC)32221003 China
CitationJournal: Sci Adv / Year: 2025
Title: An antidepressant mechanism underlying the allosteric inhibition of GluN2D-incorporated NMDA receptors at GABAergic interneurons.
Authors: Jilin Zhang / Jinjin Duan / Wei Li / Xian Wang / Shimin Ren / Luyu Ye / Fang Liu / Xiaoting Tian / Yang Xie / Yiming Huang / Yidi Sun / Nan Song / Tianyu Li / Xiang Cai / Zhiqiang Liu / Hu ...Authors: Jilin Zhang / Jinjin Duan / Wei Li / Xian Wang / Shimin Ren / Luyu Ye / Fang Liu / Xiaoting Tian / Yang Xie / Yiming Huang / Yidi Sun / Nan Song / Tianyu Li / Xiang Cai / Zhiqiang Liu / Hu Zhou / Chenggang Huang / Yang Li / Shujia Zhu / Fei Guo /
Abstract: -methyl-d-aspartate receptors (NMDARs), key excitatory ion channels, have gained attention as anti-depression targets. NMDARs consist of two GluN1 and two GluN2 subunits (2A-2D), which determine ...-methyl-d-aspartate receptors (NMDARs), key excitatory ion channels, have gained attention as anti-depression targets. NMDARs consist of two GluN1 and two GluN2 subunits (2A-2D), which determine their pharmacological properties. Few compounds selectively targeting GluN2 subunits with antidepressant effects have been identified. Here, we present YY-23, a compound that selectively inhibits GluN2C- or GluN2D-containing NMDARs. Cryo-EM analysis revealed that YY-23 binds to the transmembrane domain of the GluN2D subunit. YY-23 primarily affects GluN2D-containing NMDARs on GABAergic interneurons in the prefrontal cortex, suppressing GABAergic neurotransmission and enhancing excitatory transmission. Behavioral assays demonstrate YY-23's rapid antidepressant effects in both stress-naïve and stress-exposed models, which are lost in mice with global or selective knockout of the gene in parvalbumin-positive interneurons. These findings highlight GluN2D-containing NMDARs on GABAergic interneurons as potential depression treatment targets.
History
DepositionJan 25, 2024-
Header (metadata) releaseJan 22, 2025-
Map releaseJan 22, 2025-
UpdateFeb 4, 2026-
Current statusFeb 4, 2026Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_38847.png

Downloads & links

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Map

FileDownload / File: emd_38847.map.gz / Format: CCP4 / Size: 83.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesX (Sec.)Y (Row.)Z (Col.)
1.07 Å/pix.
x 280 pix.
= 299.88 Å		1.07 Å/pix.
x 280 pix.
= 299.88 Å		1.07 Å/pix.
x 280 pix.
= 299.88 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.071 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0123
Minimum - Maximum-0.019075792 - 0.04576813
Average (Standard dev.)0.00018440395 (±0.002284942)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderZYX
Origin000
Dimensions280280280
Spacing280280280
CellA=B=C: 299.88 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_38847_msk_1.map
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AxesZYX

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Half map: #2

Fileemd_38847_half_map_1.map
Projections & Slices
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Half map: #1

Fileemd_38847_half_map_2.map
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Sample components

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Entire : N-methyl-D-aspartate receptors

EntireName: N-methyl-D-aspartate receptors
Components
  • Complex: N-methyl-D-aspartate receptors
    • Protein or peptide: Isoform 6 of Glutamate receptor ionotropic, NMDA 1
    • Protein or peptide: Glutamate receptor ionotropic, NMDA 2D
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: (2~{R},3~{S},4~{S},5~{R},6~{R})-2-(hydroxymethyl)-6-[(2~{S})-2-methyl-4-[(1~{R},2~{R},4~{S},6~{S},7~{S},8~{R},9~{S},12~{S},13~{R},16~{S},18~{R})-7,9,13,18-tetramethyl-16-oxidanyl-5-oxapentacyclo[10.8.0.0^{2,9}.0^{4,8}.0^{13,18}]icosan-6-yl]butoxy]oxane-3,4,5-triol

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Supramolecule #1: N-methyl-D-aspartate receptors

SupramoleculeName: N-methyl-D-aspartate receptors / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 400 kDa/nm

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Macromolecule #1: Isoform 6 of Glutamate receptor ionotropic, NMDA 1

MacromoleculeName: Isoform 6 of 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: 97.777914 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 SKSKKRNYEN LDQLSYDNKR GPKAEKVLQF DPGTKNVTAL LMEAKELEAR VI ILSASED DAATVYRAAA MLNMTGSGYV WLVGEREISG NALRYAPDGI LGLQLINGKN ESAHISDAVG VVAQAVHELL EKE NITDPP RGCVGNTNIW KTGPLFKRVL MSSKYADGVT GRVEFNEDGD RKFANYSIMN LQNRKLVQVG IYNGTHVIPN DRKI IWPGG ETEKPRGYQM STRLKIVTIH QEPFVYVKPT LSDGTCKEEF TVNGDPVKKV ICTGPNDTSP GSPRHTVPQC CYGFC IDLL IKLARTMNFT YEVHLVADGK FGTQERVNNS NKKEWNGMMG ELLSGQADMI VAPLTINNER AQYIEFSKPF KYQGLT ILV KKEIPRSTLD SFMQPFQSTL WLLVGLSVHV VAVMLYLLDR FSPFGRFKVN SEEEEEDALT LSSAMWFSWG VLLNSGI GE GAPRSFSARI LGMVWAGFAM IIVASYTANL AAFLVLDRPE ERITGINDPR LRNPSDKFIY ATVKQSSVDI YFRRQVEL S TMYRHMEKHN YESAAEAIQA VRDNKLHAFI WDSAVLEFEA SQKCDLVTTG ELFFRSGFGI GMRKDSPWKQ NVSLSILKS HENGFMEDLD KTWVRYQECD SRSNAPATLT FENMAGVFML VAGGIVAGIF LIFIEIAYKR HKDARRKQ

UniProtKB: Glutamate receptor ionotropic, NMDA 1

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Macromolecule #2: Glutamate receptor ionotropic, NMDA 2D

MacromoleculeName: Glutamate receptor ionotropic, NMDA 2D / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 99.057328 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MRGAGGPRGP RGPAKMLLLL ALACASPFPE EAPGPGGAGG PGGGLGGARP LNVALVFSGP AYAAEAARLG PAVAAAVRSP GLDVRPVAL VLNGSDPRSL VLQLCDLLSG LRVHGVVFED DSRAPAVAPI LDFLSAQTSL PIVAVHGGAA LVLTPKEKGS T FLQLGSST ...String:
MRGAGGPRGP RGPAKMLLLL ALACASPFPE EAPGPGGAGG PGGGLGGARP LNVALVFSGP AYAAEAARLG PAVAAAVRSP GLDVRPVAL VLNGSDPRSL VLQLCDLLSG LRVHGVVFED DSRAPAVAPI LDFLSAQTSL PIVAVHGGAA LVLTPKEKGS T FLQLGSST EQQLQVIFEV LEEYDWTSFV AVTTRAPGHR AFLSYIEVLT DGSLVGWEHR GALTLDPGAG EAVLSAQLRS VS AQIRLLF CAREEAEPVF RAAEEAGLTG SGYVWFMVGP QLAGGGGSGA PGEPPLLPGG APLPAGLFAV RSAGWRDDLA RRV AAGVAV VARGAQALLR DYGFLPELGH DCRAQNRTHR GESLHRYFMN ITWDNRDYSF NEDGFLVNPS LVVISLTRDR TWEV VGSWE QQTLRLKYPL WSRYGRFLQP VDDTQHLTVA TLEERPFVIV EPADPISGTC IRDSVPCRSQ LNRTHSPPPD APRPE KRCC KGFCIDILKR LAHTIGFSYD LYLVTNGKHG KKIDGVWNGM IGEVFYQRAD MAIGSLTINE ERSEIVDFSV PFVETG ISV MVARSNGTVS PSAFLEPYSP AVWVMMFVMC LTVVAVTVFI FEYLSPVGYN RSLATGKRPG GSTFTIGKSI WLLWALV FN NSVPVENPRG TTSKIMVLVW AFFAVIFLAS YTANLAAFMI QEEYVDTVSG LSDRKFQRPQ EQYPPLKFGT VPNGSTEK N IRSNYPDMHS YMVRYNQPRV EEALTQLKAG KLDAFIYDAA VLNYMARKDE GCKLVTIGSG KVFATTGYGI ALHKGSRWK RPIDLALLQF LGDDEIEMLE RLWLSGICHN DKIEVMSSKL DIDNMAGVFY MLLVAMGLSL LVFAWEHLVY WRLRHCLGPA ASAWSHPQF EKGGGSGGGS GGSAWSHPQF EK

UniProtKB: Glutamate receptor ionotropic, NMDA 2D

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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: 4 / 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~{R},3~{S},4~{S},5~{R},6~{R})-2-(hydroxymethyl)-6-[(2~{S})-2-me...

MacromoleculeName: (2~{R},3~{S},4~{S},5~{R},6~{R})-2-(hydroxymethyl)-6-[(2~{S})-2-methyl-4-[(1~{R},2~{R},4~{S},6~{S},7~{S},8~{R},9~{S},12~{S},13~{R},16~{S},18~{R})-7,9,13,18-tetramethyl-16-oxidanyl-5- ...Name: (2~{R},3~{S},4~{S},5~{R},6~{R})-2-(hydroxymethyl)-6-[(2~{S})-2-methyl-4-[(1~{R},2~{R},4~{S},6~{S},7~{S},8~{R},9~{S},12~{S},13~{R},16~{S},18~{R})-7,9,13,18-tetramethyl-16-oxidanyl-5-oxapentacyclo[10.8.0.0^{2,9}.0^{4,8}.0^{13,18}]icosan-6-yl]butoxy]oxane-3,4,5-triol
type: ligand / ID: 4 / Number of copies: 2 / Formula: A1LW8
Molecular weightTheoretical: 592.804 Da

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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

Concentration2.0 mg/mL
BufferpH: 8
Sugar embeddingMaterial: nanodisc
Details: The protein sample of N-methyl-D-aspartate receptors was reconstructed into artificial nanodiscs composed by soya bean lecithin and MSP1E3D1 protein.
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 60 sec. / Pretreatment - Atmosphere: AIR
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 46.4 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: DIRECT ELECTRON DE-10 (5k x 4k) / Detector mode: SUPER-RESOLUTION / Digitization - Frames/image: 1-40 / Number grids imaged: 1 / Number real images: 6016 / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.5 µm / Nominal defocus min: 1.5 µm
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 605501
CTF correctionSoftware - Name: RELION (ver. 3.1.1) / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

7yff

Final reconstructionNumber classes used: 3 / Resolution.type: BY AUTHOR / Resolution: 4.2 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 3.1.1) / Number images used: 82019
Initial angle assignmentType: ANGULAR RECONSTITUTION / Software - Name: RELION (ver. 3.1.1)
Final angle assignmentType: ANGULAR RECONSTITUTION / Software - Name: RELION (ver. 3.1.1)
Final 3D classificationNumber classes: 5 / Avg.num./class: 22783 / Software - Name: RELION (ver. 3.1.1)
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

7yff


Chain - Source name: PDB / Chain - Initial model type: experimental model
RefinementProtocol: RIGID BODY FIT
Output model

PDB-8y1v:
Structure of GluN1b-GluN2D NMDA receptor in complex with competitive antagonist R-CPP and allosteric inhibitor YY-23

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