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- EMDB-43783: Rat GluN1-GluN2B NMDA receptor channel in complex with glutamate -

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Basic information

Entry
Database: EMDB / ID: EMD-43783
TitleRat GluN1-GluN2B NMDA receptor channel in complex with glutamate
Map dataThe B-factor sharpened map.
Sample
  • Complex: Di-heterotetrameric GluN1-GluN2B NMDA receptors
    • Protein or peptide: Isoform B of Glutamate receptor ionotropic, NMDA 1
    • Protein or peptide: Glutamate receptor ionotropic, NMDA 2B
  • Ligand: GLUTAMIC ACID
KeywordsLigand-gated ion channel / ionotropic glutamate receptor / synaptic membrane protein / MEMBRANE PROTEIN
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 / sensory organ development / regulation of protein kinase A signaling / pons maturation / positive regulation of Schwann cell migration / regulation of cell communication / sensitization ...neurotransmitter receptor activity involved in regulation of postsynaptic membrane potential / cellular response to curcumin / cellular response to corticosterone stimulus / cellular response to magnesium starvation / sensory organ development / regulation of protein kinase A signaling / pons maturation / positive regulation of Schwann cell migration / regulation of cell communication / sensitization / EPHB-mediated forward signaling / auditory behavior / Assembly and cell surface presentation of NMDA receptors / olfactory learning / conditioned taste aversion / response to hydrogen sulfide / dendritic branch / regulation of respiratory gaseous exchange / positive regulation of inhibitory postsynaptic potential / response to other organism / protein localization to postsynaptic membrane / apical dendrite / regulation of ARF protein signal transduction / fear response / response to methylmercury / response to glycine / propylene metabolic process / response to carbohydrate / interleukin-1 receptor binding / cellular response to dsRNA / negative regulation of dendritic spine maintenance / positive regulation of glutamate secretion / cellular response to lipid / voltage-gated monoatomic cation channel activity / response to growth hormone / Synaptic adhesion-like molecules / regulation of monoatomic cation transmembrane transport / NMDA glutamate receptor activity / RAF/MAP kinase cascade / response to manganese ion / transmitter-gated monoatomic ion channel activity / NMDA selective glutamate receptor complex / ligand-gated sodium channel activity / response to morphine / calcium ion transmembrane import into cytosol / glutamate binding / regulation of axonogenesis / neuromuscular process / protein heterotetramerization / male mating behavior / regulation of dendrite morphogenesis / regulation of synapse assembly / heterocyclic compound binding / glycine binding / positive regulation of reactive oxygen species biosynthetic process / positive regulation of calcium ion transport into cytosol / parallel fiber to Purkinje cell synapse / receptor clustering / suckling behavior / response to amine / startle response / small molecule binding / social behavior / associative learning / behavioral response to pain / response to magnesium ion / monoatomic cation transmembrane transport / regulation of neuronal synaptic plasticity / regulation of MAPK cascade / monoatomic cation transport / cellular response to glycine / extracellularly glutamate-gated ion channel activity / : / positive regulation of excitatory postsynaptic potential / excitatory synapse / ligand-gated monoatomic ion channel activity / action potential / regulation of postsynaptic membrane potential / positive regulation of dendritic spine maintenance / Unblocking of NMDA receptors, glutamate binding and activation / long-term memory / cellular response to manganese ion / behavioral fear response / postsynaptic density, intracellular component / glutamate receptor binding / phosphatase binding / neuron development / multicellular organismal response to stress / synaptic cleft / prepulse inhibition / monoatomic cation channel activity / detection of mechanical stimulus involved in sensory perception of pain / response to electrical stimulus / response to mechanical stimulus / calcium ion homeostasis / glutamate-gated receptor activity / response to fungicide / D2 dopamine receptor binding / cell adhesion molecule binding / presynaptic active zone membrane
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: 3.9 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: Nature / Year: 2024
Title: Molecular mechanism of ligand gating and opening of NMDA receptor.
Authors: Tsung-Han Chou / Max Epstein / Russell G Fritzemeier / Nicholas S Akins / Srinu Paladugu / Elijah Z Ullman / Dennis C Liotta / Stephen F Traynelis / Hiro Furukawa /
Abstract: Glutamate transmission and activation of ionotropic glutamate receptors are the fundamental means by which neurons control their excitability and neuroplasticity. The N-methyl-D-aspartate receptor ...Glutamate transmission and activation of ionotropic glutamate receptors are the fundamental means by which neurons control their excitability and neuroplasticity. The N-methyl-D-aspartate receptor (NMDAR) is unique among all ligand-gated channels, requiring two ligands-glutamate and glycine-for activation. These receptors function as heterotetrameric ion channels, with the channel opening dependent on the simultaneous binding of glycine and glutamate to the extracellular ligand-binding domains (LBDs) of the GluN1 and GluN2 subunits, respectively. The exact molecular mechanism for channel gating by the two ligands has been unclear, particularly without structures representing the open channel and apo states. Here we show that the channel gate opening requires tension in the linker connecting the LBD and transmembrane domain (TMD) and rotation of the extracellular domain relative to the TMD. Using electron cryomicroscopy, we captured the structure of the GluN1-GluN2B (GluN1-2B) NMDAR in its open state bound to a positive allosteric modulator. This process rotates and bends the pore-forming helices in GluN1 and GluN2B, altering the symmetry of the TMD channel from pseudofourfold to twofold. Structures of GluN1-2B NMDAR in apo and single-liganded states showed that binding of either glycine or glutamate alone leads to distinct GluN1-2B dimer arrangements but insufficient tension in the LBD-TMD linker for channel opening. This mechanistic framework identifies a key determinant for channel gating and a potential pharmacological strategy for modulating NMDAR activity.
History
DepositionFeb 23, 2024-
Header (metadata) releaseJul 31, 2024-
Map releaseJul 31, 2024-
UpdateNov 6, 2024-
Current statusNov 6, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_43783.png

Downloads & links

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Map

FileDownload / File: emd_43783.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationThe B-factor sharpened map.
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.07 Å/pix.
x 320 pix.
= 342.4 Å		1.07 Å/pix.
x 320 pix.
= 342.4 Å		1.07 Å/pix.
x 320 pix.
= 342.4 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.07 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0915
Minimum - Maximum-0.90858436 - 1.3871827
Average (Standard dev.)0.00042889247 (±0.02233989)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 342.40002 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Map A of the two half maps.

Fileemd_43783_half_map_1.map
AnnotationMap A of the two half maps.
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Map B of the two half maps.

Fileemd_43783_half_map_2.map
AnnotationMap B of the two half maps.
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Di-heterotetrameric GluN1-GluN2B NMDA receptors

EntireName: Di-heterotetrameric GluN1-GluN2B NMDA receptors
Components
  • Complex: Di-heterotetrameric GluN1-GluN2B NMDA receptors
    • Protein or peptide: Isoform B of Glutamate receptor ionotropic, NMDA 1
    • Protein or peptide: Glutamate receptor ionotropic, NMDA 2B
  • Ligand: GLUTAMIC ACID

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Supramolecule #1: Di-heterotetrameric GluN1-GluN2B NMDA receptors

SupramoleculeName: Di-heterotetrameric GluN1-GluN2B NMDA receptors / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Rattus norvegicus (Norway rat)
Molecular weightTheoretical: 400 KDa

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

MacromoleculeName: Isoform B of 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: 108.085633 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 SKSKKRNYEN LDQLSYDNKR GPKAEKVLQF DPGTKNVTAL LMEARELEAR VI ILSASED DAATVYRAAA MLDMTGSGYV WLVGEREISG NALRYAPDGI IGLQLINGKN ESAHISDAVG VVAQAVHELL EKE NITDPP RGCVGNTNIW KTGPLFKRVL MSSKYADGVT GRVEFNEDGD RKFAQYSIMN LQNRKLVQVG IYNGTHVIPN DRKI IWPGG ETEKPRGYQM STRLKIVTIH QEPFVYVKPT MSDGTCKEEF TVNGDPVKKV ICTGPNDTSP GSPRHTVPQC CYGFC IDLL IKLARTMQFT YEVHLVADGK FGTQERVQNS NKKEWNGMMG ELLSGQADMI VAPLTINNER AQYIEFSKPF KYQGLT ILV KKEIPRSTLD SFMQPFQSTL WLLVGLSVHV VAVMLYLLDR FSPFGRFKVN SQSESTDALT LSSAMWFSWG VLLNSGI GE GAPRSFSARI LGMVWAGFAM IIVASYTANL AAFLVLDRPE ERITGINDPR LRNPSDKFIY ATVKQSSVDI YFRRQVEL S TMYRHMEKHN YESAAEAIQA VRDNKLHAFI WDSAVLEFEA SQKCDLVTTG ELFFRSGFGI GMRKDSPWKQ QVSLSILKS HENGFMEDLD KTWVRYQECD SRSNAPATLT CENMAGVFML VAGGIVAGIF LIFIEIAYKR HKDARRKQMQ LAFAAVNVWR KNLQDRKSG RAEPDPKKKA TFRAITSTLA SSFKRRRSSK DTSTGGGRGA LQNQKDTVLP RRAIEREEGQ LQLCSRHRES

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: 98.845859 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 GRDLSFSEDG YQMHPKLVII LLNK ERKWE RVGKWKDKSL QMKYYVWPRM CPETEEQEDD HLSIVTLEEA PFVIVESVDP LSGTCMRNTV PCQKRIISEN KTDEE PGYI KKCCKGFCID ILKKISKSVK FTYDLYLVTN GKHGKKINGT WNGMIGEVVM KRAYMAVGSL TINEERSEVV DFSVPF IET GISVMVSRSN GTVSPSAFLE PFSACVWVMM FVMLLIVSAV AVFVFEYFSP VGYNRSLADG 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 ALSLITFISE HLFYWQFRHS FMG

UniProtKB: Glutamate receptor ionotropic, NMDA 2B

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Macromolecule #3: GLUTAMIC ACID

MacromoleculeName: GLUTAMIC ACID / type: ligand / ID: 3 / Number of copies: 2 / Formula: GLU
Molecular weightTheoretical: 147.129 Da
Chemical component information

ChemComp-GLU:
GLUTAMIC ACID

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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 K2 SUMMIT (4k x 4k) / Average electron dose: 58.8 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.8000000000000003 µm / Nominal defocus min: 1.6 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.9 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 230178
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC

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Atomic model buiding 1

Initial modelPDB ID:

7saa


Chain - Source name: PDB / Chain - Initial model type: experimental model
RefinementProtocol: BACKBONE TRACE
Output model

PDB-9ari:
Rat GluN1-GluN2B NMDA receptor channel in complex with glutamate

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