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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 chain
  • Fab, light chain
  • Glutamate receptor ionotropic, NMDA 2B
  • NMDA glutamate receptor subunit
KeywordsTRANSPORT PROTEIN / NMDA receptor
Function / homology
Function and homology information


cellular response to curcumin / cellular response to corticosterone stimulus / cellular response to magnesium starvation / sensory organ development / sensitization / EPHB-mediated forward signaling / Assembly and cell surface presentation of NMDA receptors / response to hydrogen sulfide / auditory behavior / dendritic branch ...cellular response to curcumin / cellular response to corticosterone stimulus / cellular response to magnesium starvation / sensory organ development / sensitization / EPHB-mediated forward signaling / Assembly and cell surface presentation of NMDA receptors / response to hydrogen sulfide / auditory behavior / dendritic branch / response to other organism / regulation of ARF protein signal transduction / fear response / apical dendrite / positive regulation of inhibitory postsynaptic potential / suckling behavior / response to methylmercury / response to manganese ion / response to carbohydrate / interleukin-1 receptor binding / cellular response to dsRNA / response to growth hormone / cellular response to lipid / negative regulation of dendritic spine maintenance / heterocyclic compound binding / positive regulation of glutamate secretion / regulation of monoatomic cation transmembrane transport / RAF/MAP kinase cascade / NMDA glutamate receptor activity / Synaptic adhesion-like molecules / response to glycoside / NMDA selective glutamate receptor complex / glutamate binding / ligand-gated sodium channel activity / response to zinc ion / calcium ion transmembrane import into cytosol / protein heterotetramerization / glycine binding / response to amine / regulation of cAMP/PKA signal transduction / small molecule binding / receptor clustering / parallel fiber to Purkinje cell synapse / startle response / monoatomic cation transmembrane transport / behavioral response to pain / regulation of MAPK cascade / regulation of postsynaptic membrane potential / associative learning / response to magnesium ion / action potential / extracellularly glutamate-gated ion channel activity / response to electrical stimulus / monoatomic cation transport / regulation of neuronal synaptic plasticity / glutamate receptor binding / Unblocking of NMDA receptors, glutamate binding and activation / positive regulation of excitatory postsynaptic potential / long-term memory / detection of mechanical stimulus involved in sensory perception of pain / response to mechanical stimulus / synaptic cleft / neuron development / multicellular organismal response to stress / positive regulation of synaptic transmission, glutamatergic / behavioral fear response / postsynaptic density, intracellular component / monoatomic cation channel activity / response to fungicide / glutamate-gated receptor activity / cell adhesion molecule binding / regulation of long-term synaptic depression / D2 dopamine receptor binding / cellular response to manganese ion / glutamate-gated calcium ion channel activity / presynaptic active zone membrane / response to cytokine / ionotropic glutamate receptor binding / ligand-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential / ionotropic glutamate receptor signaling pathway / cellular response to forskolin / sodium ion transmembrane transport / protein tyrosine kinase binding / synaptic membrane / response to amphetamine / hippocampal mossy fiber to CA3 synapse / learning / response to nicotine / regulation of membrane potential / response to cocaine / excitatory postsynaptic potential / transmitter-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential / synaptic transmission, glutamatergic / hippocampus development / cellular response to amino acid stimulus / regulation of long-term neuronal synaptic plasticity / postsynaptic density membrane / response to calcium ion / beta-catenin binding / cerebral cortex development
Similarity search - Function
Glutamate [NMDA] receptor, epsilon subunit, C-terminal / N-methyl D-aspartate receptor 2B3 C-terminus / : / : / Response regulator / 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 / : / : / Response regulator / 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 / 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
Revision 1.6Oct 23, 2024Group: Data collection / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / pdbx_entry_details / pdbx_modification_feature

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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


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


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


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


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

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Details

Has protein modificationY

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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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