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- PDB-7teq: Cryo-EM structure of GluN1b-2B NMDAR in complex with Fab5 active ... -

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Basic information

Entry
Database: PDB / ID: 7teq
TitleCryo-EM structure of GluN1b-2B NMDAR in complex with Fab5 active conformation
Components
  • Fab5 heavy chain
  • Fab5 light chain
  • Glutamate receptor ionotropic, NMDA 1
  • Glutamate receptor ionotropic, NMDA 2B
KeywordsSIGNALING PROTEIN/IMMUNE SYSTEM / channel / antibody / 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 / pons maturation / positive regulation of Schwann cell migration / regulation of cell communication / sensitization / EPHB-mediated forward signaling / Assembly and cell surface presentation of NMDA receptors ...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 / sensitization / EPHB-mediated forward signaling / Assembly and cell surface presentation of NMDA receptors / response to hydrogen sulfide / auditory behavior / 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 / apical dendrite / transmitter-gated monoatomic ion channel activity / positive regulation of inhibitory postsynaptic potential / suckling behavior / response to methylmercury / response to glycine / propylene metabolic process / response to manganese ion / response to carbohydrate / interleukin-1 receptor binding / negative regulation of dendritic spine maintenance / cellular response to dsRNA / response to growth hormone / cellular response to lipid / heterocyclic compound binding / regulation of monoatomic cation transmembrane transport / NMDA glutamate receptor activity / positive regulation of glutamate secretion / RAF/MAP kinase cascade / Synaptic adhesion-like molecules / voltage-gated monoatomic cation channel activity / response to glycoside / NMDA selective glutamate receptor complex / glutamate binding / ligand-gated sodium channel activity / neurotransmitter receptor complex / response to morphine / calcium ion transmembrane import into cytosol / regulation of axonogenesis / neuromuscular process / regulation of dendrite morphogenesis / protein heterotetramerization / male mating behavior / glycine binding / regulation of synapse assembly / response to amine / small molecule binding / regulation of cAMP/PKA signal transduction / parallel fiber to Purkinje cell synapse / receptor clustering / startle response / positive regulation of reactive oxygen species biosynthetic process / monoatomic cation transmembrane transport / behavioral response to pain / positive regulation of calcium ion transport into cytosol / regulation of MAPK cascade / response to magnesium ion / regulation of neuron apoptotic process / regulation of postsynaptic membrane potential / cellular response to glycine / associative learning / action potential / extracellularly glutamate-gated ion channel activity / monoatomic cation transport / excitatory synapse / positive regulation of dendritic spine maintenance / response to electrical stimulus / social behavior / regulation of neuronal synaptic plasticity / monoatomic ion channel complex / glutamate receptor binding / positive regulation of excitatory postsynaptic potential / Unblocking of NMDA receptors, glutamate binding and activation / response to mechanical stimulus / long-term memory / detection of mechanical stimulus involved in sensory perception of pain / synaptic cleft / neuron development / behavioral fear response / positive regulation of synaptic transmission, glutamatergic / prepulse inhibition / phosphatase binding / multicellular organismal response to stress / postsynaptic density, intracellular component / monoatomic cation channel activity / calcium ion homeostasis / response to fungicide / glutamate-gated receptor activity / cell adhesion molecule binding / D2 dopamine receptor 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 speciesRattus norvegicus (Norway rat)
Mus musculus (house mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 7.51 Å
AuthorsTajima, 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 5, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 2, 2022Provider: repository / Type: Initial release
Revision 1.1Oct 30, 2024Group: Data collection / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update

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Assembly

Deposited unit
A: Glutamate receptor ionotropic, NMDA 1
B: Glutamate receptor ionotropic, NMDA 2B
C: Glutamate receptor ionotropic, NMDA 1
D: Glutamate receptor ionotropic, NMDA 2B
H: Fab5 heavy chain
L: Fab5 light chain
M: Fab5 heavy chain
N: Fab5 light chain


Theoretical massNumber of molelcules
Total (without water)485,4188
Polymers485,4188
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
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: 96944.891 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: 98797.820 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: 23121.395 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Mus musculus (house mouse)
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: GluN1b-2B NMDAR complexed to Fab5 / Type: COMPLEX / Entity ID: all / Source: MULTIPLE SOURCES
Source (natural)Organism: Rattus norvegicus (Norway rat)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid type: C-flat-1.2/1.3
VitrificationCryogen name: ETHANE

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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: OTHER
Electron lensMode: OTHER / Nominal defocus max: 3000 nm / Nominal defocus min: 1500 nm
Image recordingElectron dose: 60 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING ONLY
3D reconstructionResolution: 7.51 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 13386 / Symmetry type: POINT

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