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- PDB-7eor: Structure of the human GluN1/GluN2A NMDA receptor in the glycine/... -

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Basic information

Entry
Database: PDB / ID: 7eor
TitleStructure of the human GluN1/GluN2A NMDA receptor in the glycine/glutamate/GNE-6901 bound state
Components
  • Glutamate receptor ionotropic, NMDA 1
  • Glutamate receptor ionotropic, NMDA 2A
KeywordsMEMBRANE PROTEIN / NMDA receptor
Function / homology
Function and homology information


glycine-gated cation channel activity / excitatory chemical synaptic transmission / directional locomotion / Synaptic adhesion-like molecules / protein localization to postsynaptic membrane / serotonin metabolic process / sleep / propylene metabolic process / response to glycine / Assembly and cell surface presentation of NMDA receptors ...glycine-gated cation channel activity / excitatory chemical synaptic transmission / directional locomotion / Synaptic adhesion-like molecules / protein localization to postsynaptic membrane / serotonin metabolic process / sleep / propylene metabolic process / response to glycine / Assembly and cell surface presentation of NMDA receptors / regulation of monoatomic cation transmembrane transport / Neurexins and neuroligins / NMDA glutamate receptor activity / NMDA selective glutamate receptor complex / glutamate binding / neurotransmitter receptor complex / ligand-gated sodium channel activity / glutamate receptor signaling pathway / calcium ion transmembrane import into cytosol / protein heterotetramerization / glycine binding / startle response / ligand-gated monoatomic ion channel activity / dopamine metabolic process / 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 / positive regulation of synaptic transmission, glutamatergic / synaptic cleft / calcium ion homeostasis / MECP2 regulates neuronal receptors and channels / EPHB-mediated forward signaling / glutamate-gated calcium ion channel activity / neurogenesis / excitatory synapse / sensory perception of pain / ionotropic glutamate receptor signaling pathway / Ras activation upon Ca2+ influx through NMDA receptor / cytoplasmic vesicle membrane / synaptic membrane / sodium ion transmembrane transport / positive regulation of excitatory postsynaptic potential / response to amphetamine / protein catabolic process / synaptic transmission, glutamatergic / excitatory postsynaptic potential / regulation of membrane potential / transmitter-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential / negative regulation of protein catabolic process / regulation of synaptic plasticity / brain development / visual learning / postsynaptic density membrane / response to wounding / calcium ion transmembrane transport / memory / terminal bouton / synaptic vesicle / long-term synaptic potentiation / signaling receptor activity / amyloid-beta binding / RAF/MAP kinase cascade / presynaptic membrane / dendritic spine / response to ethanol / chemical synaptic transmission / learning or memory / postsynaptic membrane / calmodulin binding / neuron projection / postsynaptic density / positive regulation of apoptotic process / response to xenobiotic stimulus / calcium ion binding / synapse / 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
Chem-6RM / 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: 4 Å
AuthorsWang, H. / Zhu, S.
Funding support China, European Union, 6items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)31771115 China
European Research Council (ERC)693021European Union
National Key R&D Program of China2017YFA0505700
Strategic Priority Research Program of Chinese Academy of SciencesXDB32020000
Shanghai Municipal Science and Technology Major Project2018SHZDZX05
Thousand Young Talents Program
CitationJournal: Neuron / Year: 2021
Title: Gating mechanism and a modulatory niche of human GluN1-GluN2A NMDA receptors.
Authors: Han Wang / Shiyun Lv / David Stroebel / Jinbao Zhang / Yijie Pan / Xuejing Huang / Xing Zhang / Pierre Paoletti / Shujia Zhu /
Abstract: N-methyl-D-aspartate (NMDA) receptors are glutamate-gated calcium-permeable ion channels that are widely implicated in synaptic transmission and plasticity. Here, we report a gallery of cryo-electron ...N-methyl-D-aspartate (NMDA) receptors are glutamate-gated calcium-permeable ion channels that are widely implicated in synaptic transmission and plasticity. Here, we report a gallery of cryo-electron microscopy (cryo-EM) structures of the human GluN1-GluN2A NMDA receptor at an overall resolution of 4 Å in complex with distinct ligands or modulators. In the full-length context of GluN1-GluN2A receptors, we visualize the competitive antagonists bound to the ligand-binding domains (LBDs) of GluN1 and GluN2A subunits, respectively. We reveal that the binding of positive allosteric modulator shortens the distance between LBDs and the transmembrane domain (TMD), which further stretches the opening of the gate. In addition, we unexpectedly visualize the binding cavity of the "foot-in-the-door" blocker 9-aminoacridine within the LBD-TMD linker region, differing from the conventional "trapping" blocker binding site at the vestibule within the TMD. Our study provides molecular insights into the crosstalk between LBDs and TMD during channel activation, inhibition, and allosteric transition.
History
DepositionApr 22, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jun 30, 2021Provider: repository / Type: Initial release
Revision 1.1Jul 14, 2021Group: Database references / Category: citation / citation_author / Item: _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Aug 18, 2021Group: Database references / Category: citation / database_2
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.3Oct 23, 2024Group: Data collection / Refinement description / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / em_3d_fitting_list / em_admin / pdbx_entry_details / pdbx_initial_refinement_model / pdbx_modification_feature
Item: _em_3d_fitting_list.accession_code / _em_3d_fitting_list.initial_refinement_model_id ..._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_entry_details.has_protein_modification

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Structure visualization

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  • Deposited structure unit
  • Imaged by Jmol
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  • Superimposition on EM map
  • EMDB-31228
  • Imaged by UCSF Chimera
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Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)385,31320
Polymers381,4964
Non-polymers3,81816
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: microscopy
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area24140 Å2
ΔGint-128 kcal/mol
Surface area156030 Å2

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Components

#1: Protein Glutamate receptor ionotropic, NMDA 2A / GluN2A / Glutamate [NMDA] receptor subunit epsilon-1 / N-methyl D-aspartate receptor subtype 2A / ...GluN2A / Glutamate [NMDA] receptor subunit epsilon-1 / N-methyl D-aspartate receptor subtype 2A / NMDAR2A / NR2A / hNR2A


Mass: 95537.703 Da / Num. of mol.: 2 / Mutation: L794C
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GRIN2A, NMDAR2A / Cell line (production host): HEK293S / Production host: Homo sapiens (human) / References: UniProt: Q12879
#2: Protein Glutamate receptor ionotropic, NMDA 1 / GluN1 / Glutamate [NMDA] receptor subunit zeta-1 / N-methyl-D-aspartate receptor subunit NR1 / NMD-R1


Mass: 95210.102 Da / Num. of mol.: 2 / Mutation: E698C
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GRIN1, NMDAR1 / Cell line (production host): HEK293S / Production host: Homo sapiens (human) / References: UniProt: Q05586
#3: Sugar
ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 14 / Source method: obtained synthetically / Formula: C8H15NO6 / Feature type: SUBJECT OF INVESTIGATION
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0
#4: Chemical ChemComp-6RM / 7-[(4-fluoranylphenoxy)methyl]-3-[(1~{R},2~{R})-2-(hydroxymethyl)cyclopropyl]-2-methyl-[1,3]thiazolo[3,2-a]pyrimidin-5-one


Mass: 360.403 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C18H17FN2O3S / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
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: Structure of the human GluN1/GluN2A NMDA receptor in the glycine/glutamate/GNE-6901 bound state
Type: COMPLEX / Entity ID: #1-#2 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human) / Cell: HEK293S
Buffer solutionpH: 8
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK III / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 281 K

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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: SPOT SCAN
Electron lensMode: BRIGHT FIELD
Image recordingElectron dose: 60 e/Å2 / Detector mode: SUPER-RESOLUTION / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.19_4092: / Classification: refinement
EM software
IDNameVersionCategory
1RELIONparticle selection
2SerialEMimage acquisition
4RELIONCTF correction
7UCSF Chimera1.14model fitting
9PHENIX1.19-4092model refinement
10RELIONinitial Euler assignment
11RELIONfinal Euler assignment
12RELIONclassification
13RELION3D reconstruction
CTF correctionType: PHASE FLIPPING ONLY
SymmetryPoint symmetry: C2 (2 fold cyclic)
3D reconstructionResolution: 4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 69419 / Symmetry type: POINT
Atomic model buildingProtocol: RIGID BODY FIT / Space: REAL
Atomic model buildingPDB-ID: 6IRA

6ira


Accession code: 6IRA / Source name: PDB / Type: experimental model
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00124702
ELECTRON MICROSCOPYf_angle_d0.38633484
ELECTRON MICROSCOPYf_dihedral_angle_d8.9658934
ELECTRON MICROSCOPYf_chiral_restr0.0413822
ELECTRON MICROSCOPYf_plane_restr0.0024202

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