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- PDB-6whw: GluN1b-GluN2B NMDA receptor in complex with GluN2B antagonist SDZ... -

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Basic information

Entry
Database: PDB / ID: 6whw
TitleGluN1b-GluN2B NMDA receptor in complex with GluN2B antagonist SDZ 220-040, class 1
Components
  • Ionotropic glutamate receptor , NMDA receptor GluN1b
  • Ionotropic glutamate receptor , NMDA receptor GluN2B
KeywordsMEMBRANE PROTEIN / NMDARs / Ligand-gated ion channels / METAL TRANSPORT / Ionotropic glutamate receptor / GluN2B antagonist
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 / sensory organ development / regulation of protein kinase A signaling / sensitization / pons maturation / positive regulation of Schwann cell migration / regulation of cell communication ...neurotransmitter receptor activity involved in regulation of postsynaptic membrane potential / cellular response to curcumin / cellular response to corticosterone stimulus / cellular response to magnesium starvation / sensory organ development / regulation of protein kinase A signaling / sensitization / pons maturation / positive regulation of Schwann cell migration / regulation of cell communication / EPHB-mediated forward signaling / Assembly and cell surface presentation of NMDA receptors / olfactory learning / conditioned taste aversion / apical dendrite / response to hydrogen sulfide / regulation of respiratory gaseous exchange / dendritic branch / positive regulation of inhibitory postsynaptic potential / response to other organism / protein localization to postsynaptic membrane / regulation of ARF protein signal transduction / fear response / response to methylmercury / propylene metabolic process / response to glycine / response to carbohydrate / negative regulation of dendritic spine maintenance / cellular response to dsRNA / interleukin-1 receptor binding / voltage-gated monoatomic cation channel activity / cellular response to lipid / regulation of monoatomic cation transmembrane transport / response to growth hormone / Synaptic adhesion-like molecules / NMDA glutamate receptor activity / positive regulation of glutamate secretion / RAF/MAP kinase cascade / response to manganese ion / NMDA selective glutamate receptor complex / ligand-gated sodium channel activity / response to morphine / calcium ion transmembrane import into cytosol / neuromuscular process / glutamate binding / protein heterotetramerization / regulation of axonogenesis / regulation of dendrite morphogenesis / male mating behavior / positive regulation of reactive oxygen species biosynthetic process / heterocyclic compound binding / regulation of synapse assembly / glycine binding / parallel fiber to Purkinje cell synapse / positive regulation of calcium ion transport into cytosol / suckling behavior / receptor clustering / monoatomic cation transmembrane transport / startle response / response to amine / small molecule binding / social behavior / regulation of neuronal synaptic plasticity / action potential / associative learning / response to magnesium ion / behavioral response to pain / monoatomic cation transport / regulation of MAPK cascade / ligand-gated monoatomic ion channel activity / cellular response to glycine / extracellularly glutamate-gated ion channel activity / : / positive regulation of excitatory postsynaptic potential / excitatory synapse / positive regulation of dendritic spine maintenance / regulation of postsynaptic membrane potential / Unblocking of NMDA receptors, glutamate binding and activation / behavioral fear response / long-term memory / cellular response to manganese ion / phosphatase binding / glutamate receptor binding / postsynaptic density, intracellular component / synaptic cleft / neuron development / monoatomic cation channel activity / multicellular organismal response to stress / detection of mechanical stimulus involved in sensory perception of pain / prepulse inhibition / response to electrical stimulus / calcium ion homeostasis / response to mechanical stimulus / glutamate-gated receptor activity / regulation of neuron apoptotic process / D2 dopamine receptor binding / response to fungicide / dendrite membrane / presynaptic active zone membrane / glutamate-gated calcium ion channel activity
Similarity search - Function
Calmodulin-binding domain C0 of NMDA receptor NR1 subunit / 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 ...Calmodulin-binding domain C0 of NMDA receptor NR1 subunit / 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
Chem-QGP / Glutamate receptor ionotropic, NMDA 1 / Glutamate receptor ionotropic, NMDA 2B
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4.09 Å
AuthorsChou, T. / Tajima, N. / Furukawa, H.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)NS111745 United States
National Institutes of Health/National Institute of Mental Health (NIH/NIMH)MH085926 United States
CitationJournal: Cell / Year: 2020
Title: Structural Basis of Functional Transitions in Mammalian NMDA Receptors.
Authors: Tsung-Han Chou / Nami Tajima / Annabel Romero-Hernandez / Hiro Furukawa /
Abstract: Excitatory neurotransmission meditated by glutamate receptors including N-methyl-D-aspartate receptors (NMDARs) is pivotal to brain development and function. NMDARs are heterotetramers composed of ...Excitatory neurotransmission meditated by glutamate receptors including N-methyl-D-aspartate receptors (NMDARs) is pivotal to brain development and function. NMDARs are heterotetramers composed of GluN1 and GluN2 subunits, which bind glycine and glutamate, respectively, to activate their ion channels. Despite importance in brain physiology, the precise mechanisms by which activation and inhibition occur via subunit-specific binding of agonists and antagonists remain largely unknown. Here, we show the detailed patterns of conformational changes and inter-subunit and -domain reorientation leading to agonist-gating and subunit-dependent competitive inhibition by providing multiple structures in distinct ligand states at 4 Å or better. The structures reveal that activation and competitive inhibition by both GluN1 and GluN2 antagonists occur by controlling the tension of the linker between the ligand-binding domain and the transmembrane ion channel of the GluN2 subunit. Our results provide detailed mechanistic insights into NMDAR pharmacology, activation, and inhibition, which are fundamental to the brain physiology.
History
DepositionApr 8, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 15, 2020Provider: repository / Type: Initial release
Revision 1.1Jul 29, 2020Group: Data collection / Derived calculations / Structure summary
Category: chem_comp / entity ...chem_comp / entity / pdbx_chem_comp_identifier / pdbx_entity_nonpoly / struct_conn / struct_site / struct_site_gen
Item: _chem_comp.name / _entity.pdbx_description ..._chem_comp.name / _entity.pdbx_description / _pdbx_entity_nonpoly.name / _struct_conn.pdbx_role
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 1.2Aug 5, 2020Group: Database references / Structure summary / Category: chem_comp / citation
Item: _chem_comp.pdbx_synonyms / _citation.journal_volume ..._chem_comp.pdbx_synonyms / _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Nov 20, 2024Group: Data collection / Database references / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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Structure visualization

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Assembly

Deposited unit
A: Ionotropic glutamate receptor , NMDA receptor GluN1b
B: Ionotropic glutamate receptor , NMDA receptor GluN2B
C: Ionotropic glutamate receptor , NMDA receptor GluN1b
D: Ionotropic glutamate receptor , NMDA receptor GluN2B
hetero molecules


Theoretical massNumber of molelcules
Total (without water)415,1468
Polymers413,8634
Non-polymers1,2834
Water00
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Ionotropic glutamate receptor , NMDA receptor GluN1b


Mass: 108085.633 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Rattus norvegicus (Norway rat) / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P35439*PLUS
#2: Protein Ionotropic glutamate receptor , NMDA receptor GluN2B


Mass: 98845.859 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Rattus norvegicus (Norway rat) / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q00960*PLUS
#3: Chemical ChemComp-QGP / (2S)-2-amino-3-[2',4'-dichloro-4-hydroxy-5-(phosphonomethyl)biphenyl-3-yl]propanoic acid


Mass: 420.181 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C16H16Cl2NO6P / Feature type: SUBJECT OF INVESTIGATION
#4: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0
Has ligand of interestY
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: NMDA receptor GluN1b/2B functional ion channel complex
Type: COMPLEX / Entity ID: #1-#2 / Source: RECOMBINANT
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 / Humidity: 85 % / Chamber temperature: 295 K

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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: FLOOD BEAM
Electron lensMode: BRIGHT FIELD
Image recordingElectron dose: 64.5 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

EM softwareName: cisTEM / Version: 1.0.0 / Category: 3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C2 (2 fold cyclic)
3D reconstructionResolution: 4.09 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 404527 / Symmetry type: POINT

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