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- PDB-7tee: Cryo-EM structure of GluN1b-2B NMDAR complexed to Fab2 Non-active... -

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Basic information

Entry
Database: PDB / ID: 7tee
TitleCryo-EM structure of GluN1b-2B NMDAR complexed to Fab2 Non-active2-like
Components
  • Fab2 heavy chain
  • Fab2 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 / positive regulation of Schwann cell migration / pons maturation / sensitization / regulation of cell communication / 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 / positive regulation of Schwann cell migration / pons maturation / sensitization / regulation of cell communication / 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 / apical dendrite / regulation of ARF protein signal transduction / fear response / protein localization to postsynaptic membrane / transmitter-gated monoatomic ion channel activity / positive regulation of inhibitory postsynaptic potential / response to methylmercury / suckling behavior / response to manganese ion / response to glycine / interleukin-1 receptor binding / response to carbohydrate / propylene metabolic process / cellular response to dsRNA / cellular response to lipid / response to growth hormone / heterocyclic compound binding / negative regulation of dendritic spine maintenance / positive regulation of glutamate secretion / RAF/MAP kinase cascade / regulation of monoatomic cation transmembrane transport / NMDA glutamate receptor activity / 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 / regulation of axonogenesis / neuromuscular process / calcium ion transmembrane import into cytosol / regulation of dendrite morphogenesis / protein heterotetramerization / male mating behavior / regulation of synapse assembly / response to amine / regulation of cAMP/PKA signal transduction / glycine binding / receptor clustering / small molecule binding / startle response / parallel fiber to Purkinje cell synapse / positive regulation of reactive oxygen species biosynthetic process / monoatomic cation transmembrane transport / behavioral response to pain / regulation of MAPK cascade / positive regulation of calcium ion transport into cytosol / cellular response to glycine / extracellularly glutamate-gated ion channel activity / regulation of postsynaptic membrane potential / response to magnesium ion / action potential / associative learning / response to electrical stimulus / excitatory synapse / positive regulation of dendritic spine maintenance / social behavior / monoatomic ion channel complex / 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 / detection of mechanical stimulus involved in sensory perception of pain / long-term memory / response to mechanical stimulus / neuron development / synaptic cleft / phosphatase binding / prepulse inhibition / positive regulation of synaptic transmission, glutamatergic / behavioral fear response / multicellular organismal response to stress / postsynaptic density, intracellular component / monoatomic cation channel activity / response to fungicide / calcium ion homeostasis / glutamate-gated receptor activity / regulation of long-term synaptic depression / regulation of neuron apoptotic process / cell adhesion molecule 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: 6.59 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 4, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 2, 2022Provider: repository / Type: Initial release
Revision 1.1Nov 6, 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: Fab2 heavy chain
L: Fab2 light chain
M: Fab2 heavy chain
N: Fab2 light chain


Theoretical massNumber of molelcules
Total (without water)486,4598
Polymers486,4598
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: Protein Fab2 heavy chain


Mass: 23914.781 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Mus musculus (house mouse)
#4: Antibody Fab2 light chain


Mass: 23572.031 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 - Fab2 / Type: COMPLEX / Entity ID: all / Source: MULTIPLE SOURCES
Molecular weightExperimental value: NO
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
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: 3500 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 65 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING ONLY
3D reconstructionResolution: 6.59 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 18851 / Symmetry type: POINT

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