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- PDB-6irf: Structure of the human GluN1/GluN2A NMDA receptor in the glutamat... -

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Basic information

Entry
Database: PDB / ID: 6irf
TitleStructure of the human GluN1/GluN2A NMDA receptor in the glutamate/glycine-bound state at pH 6.3, Class I
Components
  • Glutamate receptor ionotropic, NMDA 1
  • Glutamate receptor ionotropic, NMDA 2A
KeywordsMEMBRANE PROTEIN / ionotropic glutamate receptors / NMDA receptors / synaptic protein
Function / homology
Function and homology information


glycine-gated cation channel activity / excitatory chemical synaptic transmission / directional locomotion / serotonin metabolic process / Synaptic adhesion-like molecules / protein localization to postsynaptic membrane / sleep / response to glycine / propylene metabolic process / regulation of monoatomic cation transmembrane transport ...glycine-gated cation channel activity / excitatory chemical synaptic transmission / directional locomotion / serotonin metabolic process / Synaptic adhesion-like molecules / protein localization to postsynaptic membrane / sleep / response to glycine / propylene metabolic process / regulation of monoatomic cation transmembrane transport / Assembly and cell surface presentation of NMDA receptors / NMDA glutamate receptor activity / neurotransmitter receptor complex / NMDA selective glutamate receptor complex / Neurexins and neuroligins / ligand-gated sodium channel activity / glutamate binding / glutamate receptor signaling pathway / calcium ion transmembrane import into cytosol / protein heterotetramerization / glycine binding / positive regulation of reactive oxygen species biosynthetic process / positive regulation of calcium ion transport into cytosol / startle response / dopamine metabolic process / Negative regulation of NMDA receptor-mediated neuronal transmission / monoatomic cation transmembrane transport / Unblocking of NMDA receptors, glutamate binding and activation / regulation of neuronal synaptic plasticity / Long-term potentiation / monoatomic cation transport / excitatory synapse / positive regulation of excitatory postsynaptic potential / monoatomic ion channel complex / synaptic cleft / calcium ion homeostasis / MECP2 regulates neuronal receptors and channels / neurogenesis / glutamate-gated calcium ion channel activity / sensory perception of pain / EPHB-mediated forward signaling / sodium ion transmembrane transport / Ras activation upon Ca2+ influx through NMDA receptor / ionotropic glutamate receptor signaling pathway / response to amphetamine / cytoplasmic vesicle membrane / positive regulation of synaptic transmission, glutamatergic / regulation of membrane potential / excitatory postsynaptic potential / transmitter-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential / synaptic transmission, glutamatergic / synaptic membrane / protein catabolic process / postsynaptic density membrane / brain development / visual learning / terminal bouton / negative regulation of protein catabolic process / calcium ion transmembrane transport / regulation of synaptic plasticity / response to wounding / memory / long-term synaptic potentiation / synaptic vesicle / signaling receptor activity / amyloid-beta binding / presynaptic membrane / RAF/MAP kinase cascade / chemical synaptic transmission / dendritic spine / response to ethanol / postsynaptic membrane / learning or memory / calmodulin binding / neuron projection / postsynaptic density / positive regulation of apoptotic process / response to xenobiotic stimulus / synapse / calcium ion binding / dendrite / endoplasmic reticulum membrane / protein-containing complex binding / glutamatergic synapse / cell surface / positive regulation of transcription by RNA polymerase II / zinc ion binding / plasma membrane / cytoplasm
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 speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 5.1 Å
AuthorsZhang, J. / Chang, S. / Zhang, X. / Zhu, S.
Funding support China, 5items
OrganizationGrant numberCountry
National Basic Research Program of China (973 Program)2017YFA0504803 China
National Basic Research Program of China (973 Program)2018YFA0507700 China
National Basic Research Program of China (973 Program)2017YFA0505700 China
National Natural Science Foundation of China31771115 China
Chinese Academy of SciencesXDBS32020000 China
CitationJournal: Cell Rep / Year: 2018
Title: Structural Basis of the Proton Sensitivity of Human GluN1-GluN2A NMDA Receptors.
Authors: Jin-Bao Zhang / Shenghai Chang / Pan Xu / Miao Miao / Hangjun Wu / Youyi Zhang / Tongtong Zhang / Han Wang / Jilin Zhang / Chun Xie / Nan Song / Cheng Luo / Xing Zhang / Shujia Zhu /
Abstract: N-methyl-D-aspartate (NMDA) receptors are critical for synaptic development and plasticity. While glutamate is the primary agonist, protons can modulate NMDA receptor activity at synapses during ...N-methyl-D-aspartate (NMDA) receptors are critical for synaptic development and plasticity. While glutamate is the primary agonist, protons can modulate NMDA receptor activity at synapses during vesicle exocytosis by mechanisms that are unknown. We used cryo-electron microscopy to solve the structures of the human GluN1-GluN2A NMDA receptor at pH 7.8 and pH 6.3. Our structures demonstrate that the proton sensor predominantly resides in the N-terminal domain (NTD) of the GluN2A subunit and reveal the allosteric coupling mechanism between the proton sensor and the channel gate. Under high-pH conditions, the GluN2A-NTD adopts an "open-and-twisted" conformation. However, upon protonation at the lower pH, the GluN2A-NTD transits from an open- to closed-cleft conformation, causing rearrangements between the tetrameric NTDs and agonist-binding domains. The conformational mobility observed in our structures (presumably from protonation) is supported by molecular dynamics simulation. Our findings reveal the structural mechanisms by which protons allosterically inhibit human GluN1-GluN2A receptor activity.
History
DepositionNov 12, 2018Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jan 16, 2019Provider: repository / Type: Initial release
Revision 1.1Jun 5, 2019Group: Advisory / Data collection ...Advisory / Data collection / Derived calculations / Refinement description
Category: em_3d_fitting_list / pdbx_validate_close_contact ...em_3d_fitting_list / pdbx_validate_close_contact / struct_conn / struct_conn_type
Revision 1.2Oct 16, 2024Group: Author supporting evidence / Data collection ...Author supporting evidence / Data collection / Database references / Refinement description / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / em_3d_fitting_list / em_admin / pdbx_audit_support / pdbx_entry_details / pdbx_initial_refinement_model / pdbx_modification_feature
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _em_3d_fitting_list.accession_code / _em_3d_fitting_list.initial_refinement_model_id / _em_3d_fitting_list.source_name / _em_3d_fitting_list.type / _em_admin.last_update / _pdbx_audit_support.funding_organization

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Structure visualization

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  • EMDB-9715
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Structure viewerMolecule:
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Assembly

Deposited unit
A: Glutamate receptor ionotropic, NMDA 1
B: Glutamate receptor ionotropic, NMDA 2A
C: Glutamate receptor ionotropic, NMDA 1
D: Glutamate receptor ionotropic, NMDA 2A


Theoretical massNumber of molelcules
Total (without water)379,0574
Polymers379,0574
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: cross-linking
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area22060 Å2
ΔGint-167 kcal/mol
Surface area152730 Å2

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Components

#1: Protein Glutamate receptor ionotropic, NMDA 1 / N-methyl-D-aspartate receptor subunit NR1 / NMD-R1


Mass: 95336.219 Da / Num. of mol.: 2 / Mutation: G612R
Source method: isolated from a genetically manipulated source
Details: 2 mM Glycine / Source: (gene. exp.) Homo sapiens (human) / Gene: Grin1, NMDAR1 / Cell line (production host): HEK293S GnTl- / Production host: Homo sapiens (human) / References: UniProt: Q05586
#2: Protein Glutamate receptor ionotropic, NMDA 2A / N-methyl D-aspartate receptor subtype 2A / hNR2A


Mass: 94192.172 Da / Num. of mol.: 2 / Mutation: E656R, E657R
Source method: isolated from a genetically manipulated source
Details: 2 mM L-Glutamate / Source: (gene. exp.) Homo sapiens (human) / Gene: Grin2a / Cell line (production host): HEK293S GnTl- / Production host: Homo sapiens (human) / References: UniProt: Q12879
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Human GluN1/GluN2A NMDA receptors in the glutamate/glycine bound state at pH 6.3, Class I
Type: COMPLEX / Details: with the presence of Glycine,L-glutamate and EDTA / Entity ID: all / Source: RECOMBINANT
Molecular weightValue: 0.38 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human) / Cell: HEK293S GnTl- / Plasmid: pEG-Bacmam
Buffer solutionpH: 6.3 / Details: Solutions were made fresh.
Buffer component
IDConc.NameFormulaBuffer-ID
1150 mMsodium chlorideNaCl1
220 mMMESC6H13NO4S1
30.05 mMEDTA(HO2CCH2)2NCH2CH2N(CH2CO2H)21
40.005 mMCholesteryl Hemisuccinate Tris SaltC31H50O4(C4H11NO3)1
50.001 g/mLDigitoninC56H92O291
60.1 mMCHAPSOC32H58N2O8S1
72 mMGlycineNH2CH2COOH1
82 mML-Glutamic acid monosodium salt hydrateC5H8NNaO4(xH2O)1
SpecimenConc.: 3.5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES / Details: Tetrameric GluN1/GluN2A NMDA receptors
Specimen supportDetails: 15 mA / Grid material: GOLD / Grid mesh size: 200 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK II / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 291 K
Details: blot for 2 seconds before plunging in liquid ethane

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD
Image recordingAverage exposure time: 12 sec. / Electron dose: 56 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Num. of grids imaged: 4
Image scansMovie frames/image: 40 / Used frames/image: 1-40

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Processing

EM software
IDNameCategory
1Gautomatchparticle selection
4GctfCTF correction
7UCSF Chimeramodel fitting
13PHENIXmodel refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 722287
3D reconstructionResolution: 5.1 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 193878 / Symmetry type: POINT
Atomic model buildingProtocol: RIGID BODY FIT
Atomic model building

3D fitting-ID: 1 / Source name: PDB / Type: experimental model

IDPDB-IDPdb chain-IDAccession codeInitial refinement model-ID
14PE5

4pe5

A4PE51
25TQ0

5tq0

B5TQ02
35H8F

5h8f

A5H8F3
44PE5

4pe5

B4PE51
54PE5

4pe5

C4PE51
64PE5

4pe5

D4PE51
75H8F

5h8f

B5H8F3

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