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- PDB-5b3j: Activation of NMDA receptors and the mechanism of inhibition by i... -

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Basic information

Entry
Database: PDB / ID: 5b3j
TitleActivation of NMDA receptors and the mechanism of inhibition by ifenprodil
Components
  • Fab, heavy chainFragment antigen-binding
  • Fab, light chainFragment antigen-binding
  • Glutamate receptor ionotropic, NMDA 2B
  • NMDA glutamate receptor subunitNMDA receptor
KeywordsTRANSPORT PROTEIN / NMDA receptor
Function / homology
Function and homology information


neurotransmitter receptor activity involved in regulation of postsynaptic membrane potential / cellular response to curcumin / cellular response to corticosterone stimulus / cellular response to magnesium starvation / NMDA selective glutamate receptor signaling pathway / regulation of postsynaptic cytosolic calcium ion concentration / sensory organ development / sensitization / EPHB-mediated forward signaling / neurotransmitter receptor activity involved in regulation of postsynaptic cytosolic calcium ion concentration ...neurotransmitter receptor activity involved in regulation of postsynaptic membrane potential / cellular response to curcumin / cellular response to corticosterone stimulus / cellular response to magnesium starvation / NMDA selective glutamate receptor signaling pathway / regulation of postsynaptic cytosolic calcium ion concentration / sensory organ development / sensitization / EPHB-mediated forward signaling / neurotransmitter receptor activity involved in regulation of postsynaptic cytosolic calcium ion concentration / Assembly and cell surface presentation of NMDA receptors / regulation of protein kinase A signaling / apical dendrite / dendritic branch / response to other organism / fear response / response to methylmercury / positive regulation of cysteine-type endopeptidase activity / glutamate-gated calcium ion channel activity / cellular response to dsRNA / response to carbohydrate / regulation of monoatomic cation transmembrane transport / interleukin-1 receptor binding / negative regulation of dendritic spine maintenance / cellular response to lipid / positive regulation of glutamate secretion / NMDA glutamate receptor activity / response to growth hormone / NMDA selective glutamate receptor complex / RAF/MAP kinase cascade / Synaptic adhesion-like molecules / parallel fiber to Purkinje cell synapse / calcium ion transmembrane import into cytosol / response to manganese ion / protein heterotetramerization / glutamate binding / action potential / glycine binding / regulation of neuronal synaptic plasticity / response to zinc ion / heterocyclic compound binding / receptor clustering / suckling behavior / behavioral response to pain / startle response / response to amine / monoatomic cation transmembrane transport / small molecule binding / regulation of MAPK cascade / positive regulation of excitatory postsynaptic potential / response to magnesium ion / associative learning / monoatomic cation transport / extracellularly glutamate-gated ion channel activity / cellular response to organic cyclic compound / neuron development / regulation of postsynaptic membrane potential / Unblocking of NMDA receptors, glutamate binding and activation / long-term memory / behavioral fear response / multicellular organismal response to stress / D2 dopamine receptor binding / synaptic cleft / cellular response to manganese ion / positive regulation of synaptic transmission / detection of mechanical stimulus involved in sensory perception of pain / response to mechanical stimulus / response to electrical stimulus / glutamate-gated receptor activity / presynaptic active zone membrane / response to fungicide / monoatomic cation channel activity / cellular response to forskolin / response to organonitrogen compound / ligand-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential / response to amphetamine / ionotropic glutamate receptor binding / excitatory postsynaptic potential / hippocampal mossy fiber to CA3 synapse / ionotropic glutamate receptor signaling pathway / cell adhesion molecule binding / positive regulation of synaptic transmission, glutamatergic / response to cocaine / transmitter-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential / synaptic membrane / learning / synaptic transmission, glutamatergic / long-term synaptic potentiation / response to cytokine / hippocampus development / cellular response to amino acid stimulus / postsynaptic density membrane / regulation of long-term neuronal synaptic plasticity / regulation of synaptic plasticity / calcium channel activity / terminal bouton / intracellular calcium ion homeostasis / response to organic cyclic compound / cerebral cortex development / memory
Similarity search - Function
Glutamate [NMDA] receptor, epsilon subunit, C-terminal / N-methyl D-aspartate receptor 2B3 C-terminus / Bacterial extracellular solute-binding proteins, family 3 / Solute-binding protein family 3/N-terminal domain of MltF / Ionotropic glutamate receptor, metazoa / Ligated ion channel L-glutamate- and glycine-binding site / : / Response regulator / Ligand-gated ion channel / Ionotropic glutamate receptor, L-glutamate and glycine-binding domain ...Glutamate [NMDA] receptor, epsilon subunit, C-terminal / N-methyl D-aspartate receptor 2B3 C-terminus / Bacterial extracellular solute-binding proteins, family 3 / Solute-binding protein family 3/N-terminal domain of MltF / Ionotropic glutamate receptor, metazoa / Ligated ion channel L-glutamate- and glycine-binding site / : / Response regulator / Ligand-gated ion channel / Ionotropic glutamate receptor, L-glutamate and glycine-binding domain / Ligated ion channel L-glutamate- and glycine-binding site / 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 / Immunoglobulins / Immunoglobulin-like / Sandwich / Rossmann fold / 3-Layer(aba) Sandwich / Mainly Beta / Alpha Beta
Similarity search - Domain/homology
Glutamate receptor ionotropic, NMDA 1 / Glutamate receptor ionotropic, NMDA 2B / Glutamate receptor ionotropic, NMDA 1
Similarity search - Component
Biological speciesXenopus laevis (African clawed frog)
Rattus norvegicus (Norway rat)
Mus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.9 Å
AuthorsTajima, N. / Karakas, E. / Grant, T. / Simorowski, N. / Diaz-Avalos, R. / Grigorieff, N. / Furukawa, H.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Mental Health (NIH/NIMH)MH085926 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM105730 United States
CitationJournal: Nature / Year: 2016
Title: Activation of NMDA receptors and the mechanism of inhibition by ifenprodil.
Authors: Nami Tajima / Erkan Karakas / Timothy Grant / Noriko Simorowski / Ruben Diaz-Avalos / Nikolaus Grigorieff / Hiro Furukawa /
Abstract: The physiology of N-methyl-d-aspartate (NMDA) receptors is fundamental to brain development and function. NMDA receptors are ionotropic glutamate receptors that function as heterotetramers composed ...The physiology of N-methyl-d-aspartate (NMDA) receptors is fundamental to brain development and function. NMDA receptors are ionotropic glutamate receptors that function as heterotetramers composed mainly of GluN1 and GluN2 subunits. Activation of NMDA receptors requires binding of neurotransmitter agonists to a ligand-binding domain (LBD) and structural rearrangement of an amino-terminal domain (ATD). Recent crystal structures of GluN1-GluN2B NMDA receptors bound to agonists and an allosteric inhibitor, ifenprodil, represent the allosterically inhibited state. However, how the ATD and LBD move to activate the NMDA receptor ion channel remains unclear. Here we applied X-ray crystallography, single-particle electron cryomicroscopy and electrophysiology to rat NMDA receptors to show that, in the absence of ifenprodil, the bi-lobed structure of GluN2 ATD adopts an open conformation accompanied by rearrangement of the GluN1-GluN2 ATD heterodimeric interface, altering subunit orientation in the ATD and LBD and forming an active receptor conformation that gates the ion channel.
History
DepositionMar 1, 2016Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0May 11, 2016Provider: repository / Type: Initial release
Revision 1.1May 18, 2016Group: Database references
Revision 1.2Jun 15, 2016Group: Database references
Revision 1.3Sep 27, 2017Group: Data collection / Database references / Derived calculations
Category: citation / diffrn_detector / pdbx_struct_oper_list
Item: _citation.journal_id_CSD / _diffrn_detector.detector / _pdbx_struct_oper_list.symmetry_operation
Revision 1.4Oct 18, 2017Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.5Mar 23, 2022Group: Author supporting evidence / Database references / Category: database_2 / pdbx_audit_support
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_audit_support.funding_organization

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: NMDA glutamate receptor subunit
B: NMDA glutamate receptor subunit
C: Glutamate receptor ionotropic, NMDA 2B
E: Fab, heavy chain
D: Glutamate receptor ionotropic, NMDA 2B
F: Fab, light chain
H: Fab, heavy chain
L: Fab, light chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)263,8039
Polymers263,7808
Non-polymers231
Water1,928107
1
A: NMDA glutamate receptor subunit
C: Glutamate receptor ionotropic, NMDA 2B


Theoretical massNumber of molelcules
Total (without water)84,3002
Polymers84,3002
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2090 Å2
ΔGint-19 kcal/mol
Surface area28800 Å2
MethodPISA
2
B: NMDA glutamate receptor subunit
D: Glutamate receptor ionotropic, NMDA 2B
hetero molecules


Theoretical massNumber of molelcules
Total (without water)84,3233
Polymers84,3002
Non-polymers231
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2090 Å2
ΔGint-31 kcal/mol
Surface area28780 Å2
MethodPISA
3
E: Fab, heavy chain
F: Fab, light chain


Theoretical massNumber of molelcules
Total (without water)47,5902
Polymers47,5902
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3290 Å2
ΔGint-26 kcal/mol
Surface area18220 Å2
MethodPISA
4
H: Fab, heavy chain
L: Fab, light chain


Theoretical massNumber of molelcules
Total (without water)47,5902
Polymers47,5902
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3350 Å2
ΔGint-28 kcal/mol
Surface area18440 Å2
MethodPISA
Unit cell
Length a, b, c (Å)247.249, 79.903, 181.314
Angle α, β, γ (deg.)90.00, 127.09, 90.00
Int Tables number5
Space group name H-MC121

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Components

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Protein , 2 types, 4 molecules ABCD

#1: Protein NMDA glutamate receptor subunit / NMDA receptor


Mass: 42932.055 Da / Num. of mol.: 2 / Fragment: UNP residues 23-405 / Mutation: N61Q, N371Q
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Xenopus laevis (African clawed frog) / Gene: grin1, NR1 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q91977, UniProt: A0A1L8F5J9*PLUS
#2: Protein Glutamate receptor ionotropic, NMDA 2B / GluN2B / Glutamate [NMDA] receptor subunit epsilon-2 / N-methyl D-aspartate receptor subtype 2B / NR2B


Mass: 41367.902 Da / Num. of mol.: 2 / Fragment: UNP residues 31-394 / Mutation: N348D
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Rattus norvegicus (Norway rat) / Gene: Grin2b / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q00960

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Antibody , 2 types, 4 molecules EHFL

#3: Antibody Fab, heavy chain / Fragment antigen-binding


Mass: 23914.783 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Mus musculus (house mouse)
#4: Antibody Fab, light chain / Fragment antigen-binding


Mass: 23675.170 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Mus musculus (house mouse)

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Non-polymers , 2 types, 108 molecules

#5: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 107 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.71 Å3/Da / Density % sol: 54.59 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 4.5
Details: 0.1M sodium acetate, 27% PEG3350, 2.2M sodium formate, 0.05 M calcium chloride

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Data collection

DiffractionMean temperature: 80 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 23-ID-D / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Apr 14, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.9→50 Å / Num. obs: 57592 / % possible obs: 91.4 % / Redundancy: 4 % / Rmerge(I) obs: 0.099 / Net I/σ(I): 8.5

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Processing

Software
NameVersionClassification
PHENIX(1.10_2155: ???)refinement
HKL-2000data reduction
PHENIXdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.9→29.93 Å / SU ML: 0.41 / Cross valid method: NONE / σ(F): 1.36 / Phase error: 31.64 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.302 2668 5.04 %
Rwork0.273 --
obs0.275 52910 84.1 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.9→29.93 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms15832 0 1 107 15940
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00816264
X-RAY DIFFRACTIONf_angle_d1.06822264
X-RAY DIFFRACTIONf_dihedral_angle_d14.069566
X-RAY DIFFRACTIONf_chiral_restr0.0622640
X-RAY DIFFRACTIONf_plane_restr0.0072834
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.9-2.95270.3961090.35642279X-RAY DIFFRACTION72
2.9527-3.00940.33151310.35092378X-RAY DIFFRACTION77
3.0094-3.07080.37061330.34082563X-RAY DIFFRACTION81
3.0708-3.13750.36881380.33242643X-RAY DIFFRACTION85
3.1375-3.21040.32971350.31862737X-RAY DIFFRACTION87
3.2104-3.29060.35911310.31212730X-RAY DIFFRACTION88
3.2906-3.37940.33171310.31032731X-RAY DIFFRACTION87
3.3794-3.47870.3081520.29292700X-RAY DIFFRACTION86
3.4787-3.59090.34241410.28272705X-RAY DIFFRACTION86
3.5909-3.7190.27831550.27772734X-RAY DIFFRACTION88
3.719-3.86760.27841260.27352751X-RAY DIFFRACTION87
3.8676-4.04320.27441540.25912754X-RAY DIFFRACTION88
4.0432-4.25580.28971440.2482680X-RAY DIFFRACTION86
4.2558-4.52160.25951490.22712692X-RAY DIFFRACTION86
4.5216-4.86930.25671460.23922670X-RAY DIFFRACTION85
4.8693-5.35680.27021510.24012611X-RAY DIFFRACTION83
5.3568-6.12620.30431360.26532683X-RAY DIFFRACTION85
6.1262-7.69660.34291420.28492646X-RAY DIFFRACTION83
7.6966-29.93040.29941640.24632555X-RAY DIFFRACTION79

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