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- PDB-9arg: Rat GluN1-GluN2B NMDA receptor channel in apo conformation -

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Basic information

Entry
Database: PDB / ID: 9arg
TitleRat GluN1-GluN2B NMDA receptor channel in apo conformation
Components
  • Glutamate receptor ionotropic, NMDA 1
  • Glutamate receptor ionotropic, NMDA 2B
KeywordsMEMBRANE PROTEIN / Ligand-gated ion channel / ionotropic glutamate receptor / synaptic membrane protein
Function / homology
Function and homology information


cellular response to curcumin / cellular response to corticosterone stimulus / cellular response to magnesium starvation / sensory organ development / pons maturation / positive regulation of Schwann cell migration / regulation of cell communication / regulation of cAMP/PKA signal transduction / EPHB-mediated forward signaling / sensitization ...cellular response to curcumin / cellular response to corticosterone stimulus / cellular response to magnesium starvation / sensory organ development / pons maturation / positive regulation of Schwann cell migration / regulation of cell communication / regulation of cAMP/PKA signal transduction / EPHB-mediated forward signaling / sensitization / auditory behavior / Assembly and cell surface presentation of NMDA receptors / response to hydrogen sulfide / olfactory learning / conditioned taste aversion / dendritic branch / regulation of respiratory gaseous exchange / response to other organism / protein localization to postsynaptic membrane / regulation of ARF protein signal transduction / fear response / transmitter-gated monoatomic ion channel activity / apical dendrite / response to carbohydrate / positive regulation of inhibitory postsynaptic potential / response to methylmercury / response to glycine / propylene metabolic process / response to manganese ion / interleukin-1 receptor binding / cellular response to dsRNA / cellular response to lipid / response to glycoside / positive regulation of glutamate secretion / negative regulation of dendritic spine maintenance / response to growth hormone / 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 / heterocyclic compound binding / 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 / receptor clustering / parallel fiber to Purkinje cell synapse / small molecule binding / suckling behavior / regulation of long-term synaptic depression / positive regulation of reactive oxygen species biosynthetic process / startle response / monoatomic cation transmembrane transport / social behavior / behavioral response to pain / positive regulation of calcium ion transport into cytosol / response to magnesium ion / associative learning / regulation of postsynaptic membrane potential / regulation of MAPK cascade / action potential / cellular response to glycine / extracellularly glutamate-gated ion channel activity / monoatomic cation transport / excitatory synapse / positive regulation of dendritic spine maintenance / positive regulation of excitatory postsynaptic potential / response to electrical stimulus / 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 / behavioral fear response / response to mechanical stimulus / detection of mechanical stimulus involved in sensory perception of pain / synaptic cleft / multicellular organismal response to stress / neuron development / prepulse inhibition / phosphatase binding / postsynaptic density, intracellular component / monoatomic cation channel activity / calcium ion homeostasis / response to fungicide / glutamate-gated receptor activity / D2 dopamine receptor binding / regulation of neuron apoptotic process
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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4.05 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
DepositionFeb 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 1.3Nov 13, 2024Group: Data collection / Structure summary
Category: em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update

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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 ionotropic, NMDA 2B
D: Glutamate receptor ionotropic, NMDA 2B
C: Glutamate receptor ionotropic, NMDA 1


Theoretical massNumber of molelcules
Total (without water)388,2304
Polymers388,2304
Non-polymers00
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 ionotropic, NMDA 2B / GluN2B / Glutamate [NMDA] receptor subunit epsilon-2 / N-methyl D-aspartate receptor subtype 2B / ...GluN2B / Glutamate [NMDA] receptor subunit epsilon-2 / N-methyl D-aspartate receptor subtype 2B / NMDAR2B / NR2B


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: Q00960
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: all / Source: RECOMBINANT
Molecular weightValue: 0.400 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 type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen 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
IDNameCategory
1cryoSPARCparticle selection
2EPUimage acquisition
4cryoSPARCCTF correction
7UCSF Chimeramodel fitting
8Cootmodel fitting
10PHENIXmodel refinement
11cryoSPARCinitial Euler assignment
12cryoSPARCfinal Euler assignment
13cryoSPARCclassification
14cryoSPARC3D reconstruction
CTF correctionType: NONE
3D reconstructionResolution: 4.05 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 60195 / Symmetry type: POINT
Atomic model buildingProtocol: BACKBONE TRACE
Atomic model buildingPDB-ID: 7SAA

7saa


Accession code: 7SAA / Source name: PDB / Type: experimental model
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00221448
ELECTRON MICROSCOPYf_angle_d0.42829628
ELECTRON MICROSCOPYf_dihedral_angle_d7.36512346
ELECTRON MICROSCOPYf_chiral_restr0.0393834
ELECTRON MICROSCOPYf_plane_restr0.0043730

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