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- PDB-7te6: Crystal structure of GluN1b-2B ATD complexed to Fab5 anti-GluN2B ... -

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Basic information

Entry
Database: PDB / ID: 7te6
TitleCrystal structure of GluN1b-2B ATD complexed to Fab5 anti-GluN2B antibody
Components
  • Fab5 heavy chain
  • Fab5 light chain
  • Glutamate receptor ionotropic, NMDA 1
  • Glutamate receptor ionotropic, NMDA 2B
KeywordsSIGNALING PROTEIN/IMMUNE SYSTEM / Fab fragment complexed to the receptor / SIGNALING PROTEIN-IMMUNE SYSTEM complex
Function / homology
Function and homology information


cellular response to curcumin / cellular response to corticosterone stimulus / cellular response to magnesium starvation / sensory organ development / regulation of cAMP/PKA signal transduction / EPHB-mediated forward signaling / Assembly and cell surface presentation of NMDA receptors / response to hydrogen sulfide / auditory behavior / sensitization ...cellular response to curcumin / cellular response to corticosterone stimulus / cellular response to magnesium starvation / sensory organ development / regulation of cAMP/PKA signal transduction / EPHB-mediated forward signaling / Assembly and cell surface presentation of NMDA receptors / response to hydrogen sulfide / auditory behavior / sensitization / response to other organism / dendritic branch / fear response / response to methylmercury / apical dendrite / regulation of ARF protein signal transduction / response to manganese ion / suckling behavior / positive regulation of inhibitory postsynaptic potential / response to carbohydrate / interleukin-1 receptor binding / cellular response to dsRNA / cellular response to lipid / response to growth hormone / negative regulation of dendritic spine maintenance / RAF/MAP kinase cascade / response to amine / heterocyclic compound binding / positive regulation of glutamate secretion / Synaptic adhesion-like molecules / regulation of monoatomic cation transmembrane transport / NMDA glutamate receptor activity / 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 / small molecule binding / glycine binding / receptor clustering / startle response / parallel fiber to Purkinje cell synapse / behavioral response to pain / monoatomic cation transmembrane transport / regulation of MAPK cascade / regulation of postsynaptic membrane potential / response to magnesium ion / response to electrical stimulus / action potential / extracellularly glutamate-gated ion channel activity / associative learning / regulation of neuronal synaptic plasticity / Unblocking of NMDA receptors, glutamate binding and activation / monoatomic cation transport / glutamate receptor binding / detection of mechanical stimulus involved in sensory perception of pain / response to mechanical stimulus / long-term memory / neuron development / multicellular organismal response to stress / positive regulation of synaptic transmission, glutamatergic / postsynaptic density, intracellular component / monoatomic cation channel activity / behavioral fear response / response to fungicide / synaptic cleft / glutamate-gated receptor activity / cellular response to manganese ion / regulation of long-term synaptic depression / D2 dopamine receptor binding / glutamate-gated calcium ion channel activity / response to cytokine / presynaptic active zone membrane / ionotropic glutamate receptor binding / cell adhesion molecule binding / ionotropic glutamate receptor signaling pathway / ligand-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential / cellular response to forskolin / protein tyrosine kinase binding / synaptic membrane / positive regulation of excitatory postsynaptic potential / sodium ion transmembrane transport / hippocampal mossy fiber to CA3 synapse / response to amphetamine / learning / response to nicotine / response to cocaine / hippocampus development / synaptic transmission, glutamatergic / excitatory postsynaptic potential / cellular response to amino acid stimulus / regulation of membrane potential / transmitter-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential / response to calcium ion / cerebral cortex development / regulation of long-term neuronal synaptic plasticity / regulation of synaptic plasticity / beta-catenin binding
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 speciesXenopus laevis (African clawed frog)
Rattus norvegicus (Norway rat)
Mus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 4.55 Å
AuthorsRegan, M. / Tajima, 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 Neurological Disorders and Stroke (NIH/NINDS)NS111745 United States
CitationJournal: Nat Commun / Year: 2022
Title: Development and characterization of functional antibodies targeting NMDA receptors.
Authors: Nami Tajima / Noriko Simorowski / Remy A Yovanno / Michael C Regan / Kevin Michalski / Ricardo Gómez / Albert Y Lau / Hiro Furukawa /
Abstract: N-methyl-D-aspartate receptors (NMDARs) are critically involved in basic brain functions and neurodegeneration as well as tumor invasiveness. Targeting specific subtypes of NMDARs with distinct ...N-methyl-D-aspartate receptors (NMDARs) are critically involved in basic brain functions and neurodegeneration as well as tumor invasiveness. Targeting specific subtypes of NMDARs with distinct activities has been considered an effective therapeutic strategy for neurological disorders and diseases. However, complete elimination of off-target effects of small chemical compounds has been challenging and thus, there is a need to explore alternative strategies for targeting NMDAR subtypes. Here we report identification of a functional antibody that specifically targets the GluN1-GluN2B NMDAR subtype and allosterically down-regulates ion channel activity as assessed by electrophysiology. Through biochemical analysis, x-ray crystallography, single-particle electron cryomicroscopy, and molecular dynamics simulations, we show that this inhibitory antibody recognizes the amino terminal domain of the GluN2B subunit and increases the population of the non-active conformational state. The current study demonstrates that antibodies may serve as specific reagents to regulate NMDAR functions for basic research and therapeutic objectives.
History
DepositionJan 4, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 2, 2022Provider: repository / Type: Initial release
Revision 1.1Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Glutamate receptor ionotropic, NMDA 1
B: Glutamate receptor ionotropic, NMDA 2B
C: Fab5 heavy chain
D: Fab5 light chain
E: Glutamate receptor ionotropic, NMDA 1
F: Glutamate receptor ionotropic, NMDA 2B
G: Fab5 heavy chain
H: Fab5 light chain


Theoretical massNumber of molelcules
Total (without water)264,0008
Polymers264,0008
Non-polymers00
Water00
1
A: Glutamate receptor ionotropic, NMDA 1
B: Glutamate receptor ionotropic, NMDA 2B
C: Fab5 heavy chain
D: Fab5 light chain


Theoretical massNumber of molelcules
Total (without water)132,0004
Polymers132,0004
Non-polymers00
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
E: Glutamate receptor ionotropic, NMDA 1
F: Glutamate receptor ionotropic, NMDA 2B
G: Fab5 heavy chain
H: Fab5 light chain


Theoretical massNumber of molelcules
Total (without water)132,0004
Polymers132,0004
Non-polymers00
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)124.922, 124.922, 407.119
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number92
Space group name H-MP41212

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Components

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


Mass: 42932.055 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Xenopus laevis (African clawed frog) / Gene: grin1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: A0A1L8F5J9
#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: 41367.902 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
#3: Antibody Fab5 heavy chain


Mass: 23844.684 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Mus musculus (house mouse)
#4: Antibody Fab5 light chain


Mass: 23855.256 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Mus musculus (house mouse)

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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: 3.01 Å3/Da / Density % sol: 59.11 %
Crystal growTemperature: 290 K / Method: vapor diffusion, hanging drop
Details: 2.1 M sodium/potassium phosphate, 100 mM lithium sulfate, 100 mM CAPS, pH 10.5, 4% formamide

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 23-ID-B / Wavelength: 1.1 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Oct 10, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.1 Å / Relative weight: 1
ReflectionResolution: 4.54→30 Å / Num. obs: 17965 / % possible obs: 97.5 % / Redundancy: 7.7 % / Rmerge(I) obs: 0.156 / Net I/σ(I): 6.2
Reflection shellResolution: 4.54→4.66 Å / Num. unique obs: 1644 / CC1/2: 0.534

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Processing

Software
NameVersionClassification
HKL-2000data reduction
PHENIX1.13_2998refinement
PDB_EXTRACT3.27data extraction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entries 5B3J & 3QEL

5b3j

3qel


Resolution: 4.55→24.984 Å / SU ML: 0.77 / Cross valid method: THROUGHOUT / σ(F): 1.36 / Phase error: 33.7 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.3242 916 5.1 %
Rwork0.2816 17049 -
obs0.2838 17965 93.27 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 222.11 Å2 / Biso mean: 83.7583 Å2 / Biso min: 38.55 Å2
Refinement stepCycle: final / Resolution: 4.55→24.984 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms17193 0 0 0 17193
Num. residues----2206
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
4.5505-4.78880.42681070.33181772
4.7888-5.08650.37131180.3196216285
5.0865-5.47540.39311280.304246596
5.4754-6.01940.36071350.31432578100
6.0194-6.87450.32711370.30862595100
6.8745-8.6020.25191420.25332648100
8.602-24.9840.25841490.2269278499

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