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- EMDB-9164: Triheteromeric NMDA receptor GluN1/GluN2A/GluN2A* in the '2-Knuck... -

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Entry
Database: EMDB / ID: EMD-9164
TitleTriheteromeric NMDA receptor GluN1/GluN2A/GluN2A* in the '2-Knuckle-Symmetric' conformation, in complex with glycine and glutamate, in the presence of 1 micromolar zinc chloride, and at pH 7.4
Map dataTriheteromeric NMDA receptor GluN1/GluN2A/GluN2A* in the '2-Knuckle-Symmetric' conformation, in complex with glycine and glutamate, in the presence of 1 micromolar zinc chloride, and at pH 7.4
Sample
  • Complex: Triheteromeric NMDA receptor GluN1/GluN2A/GluN2A* in the '2-Knuckle-Symmetric' conformation, in complex with glycine and glutamate, in the presence of 1 micromolar zinc chloride, and at pH 7.4
    • Protein or peptide: Glutamate receptor ionotropic, NMDA 1
    • Protein or peptide: Glutamate receptor ionotropic, NMDA 2A
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
KeywordsLigand-gated Ion Channel / NMDA Receptor / ionotropic Glutamate Receptors / membrane protein / TRANSPORT PROTEIN
Function / homology
Function and homology information


neurotransmitter receptor transport, plasma membrane to endosome / regulation of response to alcohol / response to ammonium ion / receptor recycling / directional locomotion / pons maturation / response to environmental enrichment / positive regulation of Schwann cell migration / regulation of cell communication / EPHB-mediated forward signaling ...neurotransmitter receptor transport, plasma membrane to endosome / regulation of response to alcohol / response to ammonium ion / receptor recycling / directional locomotion / pons maturation / response to environmental enrichment / positive regulation of Schwann cell migration / regulation of cell communication / EPHB-mediated forward signaling / auditory behavior / Assembly and cell surface presentation of NMDA receptors / serotonin metabolic process / 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 / cellular response to magnesium ion / regulation of ARF protein signal transduction / response to methylmercury / conditioned place preference / locomotion / dendritic spine organization / response to glycine / propylene metabolic process / response to carbohydrate / sleep / regulation of NMDA receptor activity / cellular response to dsRNA / cellular response to lipid / voltage-gated monoatomic cation channel activity / 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 / cellular response to zinc ion / ligand-gated sodium channel activity / response to morphine / glutamate receptor signaling pathway / 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 / spinal cord development / glycine binding / positive regulation of reactive oxygen species biosynthetic process / positive regulation of calcium ion transport into cytosol / parallel fiber to Purkinje cell synapse / suckling behavior / response to amine / startle response / dopamine metabolic process / social behavior / modulation of excitatory postsynaptic potential / response to lithium ion / associative learning / monoatomic cation transmembrane transport / regulation of neuronal synaptic plasticity / monoatomic cation transport / response to light stimulus / cellular response to glycine / positive regulation of excitatory postsynaptic potential / excitatory synapse / ligand-gated monoatomic ion channel activity / action potential / positive regulation of protein targeting to membrane / 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 / postsynaptic density, intracellular component / glutamate receptor binding / phosphatase binding / neuron development / multicellular organismal response to stress / synaptic cleft / prepulse inhibition / monoatomic cation channel activity / calcium ion homeostasis / glutamate-gated receptor activity / response to fungicide / cell adhesion molecule binding / presynaptic active zone membrane / regulation of neuron apoptotic process / dendrite membrane / glutamate-gated calcium ion channel activity / sensory perception of pain / ligand-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential
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 2A
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat)
Methodsingle particle reconstruction / cryo EM / Resolution: 6.2 Å
AuthorsJalali-Yazdi F / Chowdhury S
Funding support United States, 2 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)R01NS038631 United States
National Institutes of Health/National Institute of Mental Health (NIH/NIMH)1F32MH115595 United States
CitationJournal: Cell / Year: 2018
Title: Mechanisms for Zinc and Proton Inhibition of the GluN1/GluN2A NMDA Receptor.
Authors: Farzad Jalali-Yazdi / Sandipan Chowdhury / Craig Yoshioka / Eric Gouaux /
Abstract: N-methyl-D-aspartate receptors (NMDARs) play essential roles in memory formation, neuronal plasticity, and brain development, with their dysfunction linked to a range of disorders from ischemia to ...N-methyl-D-aspartate receptors (NMDARs) play essential roles in memory formation, neuronal plasticity, and brain development, with their dysfunction linked to a range of disorders from ischemia to schizophrenia. Zinc and pH are physiological allosteric modulators of NMDARs, with GluN2A-containing receptors inhibited by nanomolar concentrations of divalent zinc and by excursions to low pH. Despite the widespread importance of zinc and proton modulation of NMDARs, the molecular mechanism by which these ions modulate receptor activity has proven elusive. Here, we use cryoelectron microscopy to elucidate the structure of the GluN1/GluN2A NMDAR in a large ensemble of conformations under a range of physiologically relevant zinc and proton concentrations. We show how zinc binding to the amino terminal domain elicits structural changes that are transduced though the ligand-binding domain and result in constriction of the ion channel gate.
History
DepositionOct 1, 2018-
Header (metadata) releaseOct 24, 2018-
Map releaseNov 28, 2018-
UpdateOct 23, 2024-
Current statusOct 23, 2024Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 4.5
  • Imaged by UCSF Chimera
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  • Surface view colored by height
  • Surface level: 4.5
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6mmw
  • Surface level: 4.5
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Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_9164.png

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Map

FileDownload / File: emd_9164.map.gz / Format: CCP4 / Size: 27 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationTriheteromeric NMDA receptor GluN1/GluN2A/GluN2A* in the '2-Knuckle-Symmetric' conformation, in complex with glycine and glutamate, in the presence of 1 micromolar zinc chloride, and at pH 7.4
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.71 Å/pix.
x 192 pix.
= 328.32 Å		1.71 Å/pix.
x 192 pix.
= 328.32 Å		1.71 Å/pix.
x 192 pix.
= 328.32 Å

Surface

Projections

Slices (1/3)

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Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.71 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 4.5 / Movie #1: 4.5
Minimum - Maximum-12.015267 - 19.317634999999999
Average (Standard dev.)0.000000000007048 (±1.0)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions192192192
Spacing192192192
CellA=B=C: 328.32 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.711.711.71
M x/y/z192192192
origin x/y/z0.0000.0000.000
length x/y/z328.320328.320328.320
α/β/γ90.00090.00090.000
start NX/NY/NZ-64-64-64
NX/NY/NZ128128128
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS192192192
D min/max/mean-12.01519.3180.000

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Supplemental data

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Mask #1

Fileemd_9164_msk_1.map
Projections & Slices
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Histogram (log scale)

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Half map: Half-maps used for FSC calculations

Fileemd_9164_half_map_1.map
AnnotationHalf-maps used for FSC calculations
Projections & Slices
AxesZYX

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Density Histograms

Histogram

Histogram (log scale)

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Half map: Half-maps used for FSC calculations

Fileemd_9164_half_map_2.map
AnnotationHalf-maps used for FSC calculations
Projections & Slices
AxesZYX

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Sample components

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Entire : Triheteromeric NMDA receptor GluN1/GluN2A/GluN2A* in the '2-Knuck...

EntireName: Triheteromeric NMDA receptor GluN1/GluN2A/GluN2A* in the '2-Knuckle-Symmetric' conformation, in complex with glycine and glutamate, in the presence of 1 micromolar zinc chloride, and at pH 7.4
Components
  • Complex: Triheteromeric NMDA receptor GluN1/GluN2A/GluN2A* in the '2-Knuckle-Symmetric' conformation, in complex with glycine and glutamate, in the presence of 1 micromolar zinc chloride, and at pH 7.4
    • Protein or peptide: Glutamate receptor ionotropic, NMDA 1
    • Protein or peptide: Glutamate receptor ionotropic, NMDA 2A
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: Triheteromeric NMDA receptor GluN1/GluN2A/GluN2A* in the '2-Knuck...

SupramoleculeName: Triheteromeric NMDA receptor GluN1/GluN2A/GluN2A* in the '2-Knuckle-Symmetric' conformation, in complex with glycine and glutamate, in the presence of 1 micromolar zinc chloride, and at pH 7.4
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Details: Sample was heterologously expressed in TSA-201 cells, detergent solubilized, and affinity purified serially to obtain the triheteromeric receptor
Source (natural)Organism: Rattus norvegicus (Norway rat)
Molecular weightTheoretical: 500 KDa

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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: 94.189781 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MSTMHLLTFA LLFSCSFARA ACDPKIVNIG AVLSTRKHEQ MFREAVNQAN KRHGSWKIQL NATSVTHKPN AIQMALSVCE DLISSQVYA ILVSHPPTPN DHFTPTPVSY TAGFYRIPVL GLTTRMSIYS DKSIHLSFLR TVPPYSHQSS VWFEMMRVYN W NHIILLVS ...String:
MSTMHLLTFA LLFSCSFARA ACDPKIVNIG AVLSTRKHEQ MFREAVNQAN KRHGSWKIQL NATSVTHKPN AIQMALSVCE DLISSQVYA ILVSHPPTPN DHFTPTPVSY TAGFYRIPVL GLTTRMSIYS DKSIHLSFLR TVPPYSHQSS VWFEMMRVYN W NHIILLVS DDHEGRAAQK RLETLLEERE SKAEKVLQFD PGTKNVTALL MEARELEARV IILSASEDDA ATVYRAAAML NM TGSGYVW LVGEREISGN ALRYAPDGII GLQLINGKNE SAHISDAVGV VAQAVHELLE KENITDPPRG CVGNTNIWKT GPL FKRVLM SSKYADGVTG RVEFNEDGDR KFANYSIMNL QNRKLVQVGI YNGTHVIPND RKIIWPGGET EKPRGYQMST RLKI VTIHQ EPFVYVKPTM 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 IFIEIAYK

UniProtKB: Glutamate receptor ionotropic, NMDA 1

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Macromolecule #2: Glutamate receptor ionotropic, NMDA 2A

MacromoleculeName: Glutamate receptor ionotropic, NMDA 2A / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Rattus norvegicus (Norway rat)
Molecular weightTheoretical: 93.630258 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MGRLGYWTLL VLPALLVWRD PAQNAAAEKG PPALNIAVLL GHSHDVTERE LRNLWGPEQA TGLPLDVNVV ALLMNRTDPK SLITHVCDL MSGARIHGLV FGDDTDQEAV AQMLDFISSQ TFIPILGIAG GASMIMADKD PTSTFFQFGA SIQQQATVML K IMQDYDWH ...String:
MGRLGYWTLL VLPALLVWRD PAQNAAAEKG PPALNIAVLL GHSHDVTERE LRNLWGPEQA TGLPLDVNVV ALLMNRTDPK SLITHVCDL MSGARIHGLV FGDDTDQEAV AQMLDFISSQ TFIPILGIAG GASMIMADKD PTSTFFQFGA SIQQQATVML K IMQDYDWH VFSLVTTIFP GYRDFISFIK TTVDNSFVGW DMQNVITLDT SFEDAKTQVQ LKKIHSSVIL LYCSKDEAVL IL SEARSLG LTGYDFFWIV PSLVSGNTEL IPKEFPSGLI SVSYDDWDYS LEARVRDGLG ILTTAASSML EKFSYIPEAK ASC YGQAEK PETPLHTLHQ FMVNVTWDGK DLSFTEEGYQ VHPRLVVIVL NKDREWEKVG KWENQTLSLR HAVWPRYKSF SDCE PDDNH LSIVTLEEAP FVIVEDIDPL TETCVRNTVP CRKFVKINNS TNEGMNVKKC CKGFCIDILK KLSRTVKFTY DLYLV TNGK HGKKVNNVWN GMIGEVVYQR AVMAVGSLTI NEERSEVVDF SVPFVETGIS VMVSRSNGTV SPSAFLEPFS ASVWVM MFV MLLIVSAIAV FVFEYFSPVG YNRNLAKGKA PHGPSFTIGK AIWLLWGLVF NNSVPVQNPK GTTSKIMVSV WAFFAVI FL ASYTANLAAF MIQEEFVDQV TGLSDKKFQR PHDYSPPFRF GTVPAGSTER NIRNNYPYMH QYMTRFNQRG VEDALVSL K TGKLDAFIYD AAVLNYKAGR DEGCKLVTIG SGYIFATTGY GIALQKGSPW KRQIDLALLQ FVGDGEMEEL ETLWLTGIC HNEKNEVMSS QLDIDNMAGV FYMLAAAMAL SLITFIW

UniProtKB: Glutamate receptor ionotropic, NMDA 2A

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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: 30 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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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

Concentration4.0 mg/mL
BufferpH: 7.4
Component:
ConcentrationFormulaName
150.0 mMNaClSodium Chloride
20.0 mMC8H18N2O4SHEPES
1.0 mg/mLC56H92O29Digitonin
1.0 uMZnCl2Zinc Chloride
GridSupport film - Material: CARBON / Support film - topology: HOLEY / Details: unspecified
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 291 K / Instrument: FEI VITROBOT MARK IV
Details: Sample was blotted for 3 seconds at blot force 1..
DetailsThis sample was monodisperse

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 BASE (4k x 4k) / Number grids imaged: 1 / Number real images: 1891 / Average exposure time: 22.0 sec. / Average electron dose: 52.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Details: Cleaned-up particles were used in CryoSPARC for de novo model generation.
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Algorithm: FOURIER SPACE / Resolution.type: BY AUTHOR / Resolution: 6.2 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cisTEM / Number images used: 58461
Initial angle assignmentType: RANDOM ASSIGNMENT / Software - Name: RELION
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION
Final 3D classificationSoftware - Name: RELION

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Atomic model buiding 1

Initial model
PDB IDChain

4pe5

chain_id: A, residue_range: 25-830, source_name: PDB, initial_model_type: experimental model

5tq0

chain_id: B, residue_range: 34-388, source_name: PDB, initial_model_type: experimental model

5i57

chain_id: A, residue_range: 3-288, source_name: PDB, initial_model_type: experimental model

5uow

chain_id: B, residue_range: 25-832, source_name: PDB, initial_model_type: experimental model
RefinementProtocol: RIGID BODY FIT
Output model

PDB-6mmw:
Triheteromeric NMDA receptor GluN1/GluN2A/GluN2A* in the '2-Knuckle-Symmetric' conformation, in complex with glycine and glutamate, in the presence of 1 micromolar zinc chloride, and at pH 7.4

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