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- PDB-9bib: Rat GluN1-GluN2B NMDA receptor channel in complex with glycine, g... -

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Basic information

Entry
Database: PDB / ID: 9bib
TitleRat GluN1-GluN2B NMDA receptor channel in complex with glycine, glutamate, and EU-1622-A, in open-channel conformation, C1 symmetry
Components
  • Glutamate receptor
  • Glutamate receptor ionotropic, NMDA 1
KeywordsMEMBRANE PROTEIN / Ionotropic glutamate receptor / synaptic membrane protein
Function / homology
Function and homology information


pons maturation / positive regulation of Schwann cell migration / regulation of cell communication / EPHB-mediated forward signaling / Assembly and cell surface presentation of NMDA receptors / olfactory learning / conditioned taste aversion / dendritic branch / regulation of respiratory gaseous exchange / protein localization to postsynaptic membrane ...pons maturation / positive regulation of Schwann cell migration / regulation of cell communication / EPHB-mediated forward signaling / Assembly and cell surface presentation of NMDA receptors / olfactory learning / conditioned taste aversion / dendritic branch / regulation of respiratory gaseous exchange / protein localization to postsynaptic membrane / transmitter-gated monoatomic ion channel activity / response to glycine / propylene metabolic process / response to glycoside / regulation of monoatomic cation transmembrane transport / NMDA glutamate receptor activity / Synaptic adhesion-like molecules / RAF/MAP kinase cascade / voltage-gated monoatomic cation channel activity / neurotransmitter receptor complex / NMDA selective glutamate receptor complex / ligand-gated sodium channel activity / glutamate binding / response to morphine / regulation of axonogenesis / calcium ion transmembrane import into cytosol / neuromuscular process / regulation of dendrite morphogenesis / regulation of synapse assembly / protein heterotetramerization / male mating behavior / glycine binding / response to amine / parallel fiber to Purkinje cell synapse / suckling behavior / positive regulation of reactive oxygen species biosynthetic process / startle response / monoatomic cation transmembrane transport / social behavior / positive regulation of calcium ion transport into cytosol / associative learning / cellular response to glycine / monoatomic cation transport / excitatory synapse / positive regulation of dendritic spine maintenance / positive regulation of excitatory postsynaptic potential / regulation of neuronal synaptic plasticity / monoatomic ion channel complex / cellular response to manganese ion / long-term memory / Unblocking of NMDA receptors, glutamate binding and activation / glutamate receptor binding / synaptic cleft / prepulse inhibition / phosphatase binding / monoatomic cation channel activity / calcium ion homeostasis / response to fungicide / glutamate-gated receptor activity / regulation of neuron apoptotic process / presynaptic active zone membrane / glutamate-gated calcium ion channel activity / sensory perception of pain / ligand-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential / dendrite membrane / sodium ion transmembrane transport / response to amphetamine / ionotropic glutamate receptor signaling pathway / positive regulation of synaptic transmission, glutamatergic / hippocampal mossy fiber to CA3 synapse / learning / adult locomotory behavior / excitatory postsynaptic potential / regulation of membrane potential / transmitter-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential / synaptic transmission, glutamatergic / synaptic membrane / regulation of long-term neuronal synaptic plasticity / modulation of chemical synaptic transmission / postsynaptic density membrane / visual learning / cerebral cortex development / calcium ion transmembrane transport / regulation of synaptic plasticity / calcium channel activity / memory / neuron cellular homeostasis / terminal bouton / intracellular calcium ion homeostasis / response to calcium ion / synaptic vesicle membrane / calcium ion transport / rhythmic process / synaptic vesicle / signaling receptor activity / amyloid-beta binding / presynaptic membrane / protein-containing complex assembly / chemical synaptic transmission / response to ethanol
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
GLUTAMIC ACID / GLYCINE / Glutamate receptor / Glutamate receptor ionotropic, NMDA 1
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.81 Å
AuthorsChou, T.-H. / Furukawa, H.
Funding support United States, 2items
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
DepositionApr 23, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 31, 2024Provider: repository / Type: Initial release
Revision 1.1Aug 7, 2024Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.title / _citation.year / _em_admin.last_update
Revision 1.2Aug 14, 2024Group: Data collection / Database references / Category: citation / em_admin
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _em_admin.last_update
Revision 1.3Oct 30, 2024Group: Data collection / Structure summary
Category: em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)388,6748
Polymers388,2304
Non-polymers4444
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Glutamate receptor ionotropic, NMDA 1 / GluN1 / Glutamate [NMDA] receptor subunit zeta-1 / N-methyl-D-aspartate receptor subunit NR1 / NMD-R1


Mass: 95225.883 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Rattus norvegicus (Norway rat) / Gene: Grin1, Nmdar1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P35439
#2: Protein Glutamate receptor


Mass: 98888.945 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Rattus norvegicus (Norway rat) / Gene: Grin2b / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: G3V746
#3: Chemical ChemComp-GLY / GLYCINE


Type: peptide linking / Mass: 75.067 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H5NO2 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-GLU / GLUTAMIC ACID


Type: L-peptide linking / Mass: 147.129 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C5H9NO4 / 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: Di-heterotetrameric GluN1-GluN2B NMDA receptors / Type: COMPLEX / Entity ID: #1-#2 / Source: RECOMBINANT
Molecular weightValue: 0.4 MDa / Experimental value: NO
Source (natural)Organism: Rattus norvegicus (Norway rat)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.5
SpecimenConc.: 4 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: UltrAuFoil R1.2/1.3
VitrificationCryogen name: ETHANE / Humidity: 85 % / Chamber temperature: 285 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: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2800 nm / Nominal defocus min: 1400 nm
Image recordingElectron dose: 66.3 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

EM software
IDNameVersionCategory
1cryoSPARCparticle selection
2EPUimage acquisition
7Cootmodel fitting
9cryoSPARCinitial Euler assignment
10cryoSPARCfinal Euler assignment
12cryoSPARC3D reconstruction
13PHENIX1.15.2model refinement
CTF correctionType: NONE
Particle selectionNum. of particles selected: 1426240
3D reconstructionResolution: 3.81 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 293641 / Symmetry type: POINT
Atomic model buildingProtocol: RIGID BODY FIT / Space: REAL
Atomic model buildingPDB-ID: 9ARE

9are


Accession code: 9ARE / Source name: PDB / Type: experimental model
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00119640
ELECTRON MICROSCOPYf_angle_d0.35627082
ELECTRON MICROSCOPYf_dihedral_angle_d7.10711273
ELECTRON MICROSCOPYf_chiral_restr0.043419
ELECTRON MICROSCOPYf_plane_restr0.0033558

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