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- PDB-6whv: GluN1b-GluN2B NMDA receptor in complex with SDZ 220-040 and L689,... -

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Basic information

Entry
Database: PDB / ID: 6whv
TitleGluN1b-GluN2B NMDA receptor in complex with SDZ 220-040 and L689,560, class 2
Components(Glutamate receptor ionotropic, NMDA ...) x 2
KeywordsMEMBRANE PROTEIN / NMDARs / Ligand-gated ion channels / METAL TRANSPORT / Ionotropic glutamate receptor / GluN1 antagonist / GluN2B antagonist
Function / homology
Function and homology information


cellular response to corticosterone stimulus / cellular response to magnesium starvation / sensory organ development / cellular response to curcumin / regulation of cAMP/PKA signal transduction / pons maturation / EPHB-mediated forward signaling / Assembly and cell surface presentation of NMDA receptors / positive regulation of Schwann cell migration / regulation of cell communication ...cellular response to corticosterone stimulus / cellular response to magnesium starvation / sensory organ development / cellular response to curcumin / regulation of cAMP/PKA signal transduction / pons maturation / EPHB-mediated forward signaling / Assembly and cell surface presentation of NMDA receptors / positive regulation of Schwann cell migration / regulation of cell communication / auditory behavior / sensitization / olfactory learning / response to methylmercury / response to other organism / response to hydrogen sulfide / fear response / dendritic branch / conditioned taste aversion / protein localization to postsynaptic membrane / regulation of ARF protein signal transduction / apical dendrite / suckling behavior / transmitter-gated monoatomic ion channel activity / response to manganese ion / interleukin-1 receptor binding / response to carbohydrate / regulation of respiratory gaseous exchange / cellular response to lipid / propylene metabolic process / response to glycine / response to growth hormone / cellular response to dsRNA / RAF/MAP kinase cascade / negative regulation of dendritic spine maintenance / positive regulation of inhibitory postsynaptic potential / neurotransmitter receptor complex / heterocyclic compound binding / response to amine / Synaptic adhesion-like molecules / response to glycoside / regulation of monoatomic cation transmembrane transport / NMDA glutamate receptor activity / NMDA selective glutamate receptor complex / glutamate binding / voltage-gated monoatomic cation channel activity / neuromuscular process / ligand-gated sodium channel activity / regulation of axonogenesis / calcium ion transmembrane import into cytosol / response to morphine / positive regulation of glutamate secretion / male mating behavior / regulation of dendrite morphogenesis / protein heterotetramerization / positive regulation of reactive oxygen species biosynthetic process / regulation of synapse assembly / small molecule binding / glycine binding / startle response / receptor clustering / parallel fiber to Purkinje cell synapse / regulation of neuronal synaptic plasticity / regulation of MAPK cascade / regulation of postsynaptic membrane potential / associative learning / behavioral response to pain / positive regulation of calcium ion transport into cytosol / extracellularly glutamate-gated ion channel activity / cellular response to glycine / response to electrical stimulus / positive regulation of dendritic spine maintenance / action potential / monoatomic cation transmembrane transport / multicellular organismal response to stress / response to magnesium ion / Unblocking of NMDA receptors, glutamate binding and activation / neuron development / detection of mechanical stimulus involved in sensory perception of pain / monoatomic cation transport / glutamate receptor binding / response to mechanical stimulus / social behavior / ligand-gated monoatomic ion channel activity / behavioral fear response / prepulse inhibition / phosphatase binding / long-term memory / postsynaptic density, intracellular component / calcium ion homeostasis / synaptic cleft / response to fungicide / monoatomic cation channel activity / adult locomotory behavior / cellular response to manganese ion / glutamate-gated receptor activity / regulation of long-term synaptic depression / positive regulation of synaptic transmission, glutamatergic / glutamate-gated calcium ion channel activity / presynaptic active zone membrane
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 / Ligand-gated ion channel / Ionotropic glutamate receptor, L-glutamate and glycine-binding domain / Ligated ion channel L-glutamate- and glycine-binding site ...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 / Ligand-gated ion channel / Ionotropic glutamate receptor, L-glutamate and glycine-binding domain / Ligated ion channel L-glutamate- and glycine-binding site / : / 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-QGM / 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: 4.05 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 1.0Aug 5, 2020Provider: repository / Type: Initial release
Revision 1.1Nov 13, 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: Glutamate receptor ionotropic, NMDA 1
B: Glutamate receptor ionotropic, NMDA 2B
C: Glutamate receptor ionotropic, NMDA 1
D: Glutamate receptor ionotropic, NMDA 2B
hetero molecules


Theoretical massNumber of molelcules
Total (without water)416,39312
Polymers413,8634
Non-polymers2,5308
Water00
1


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

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Components

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Glutamate receptor ionotropic, NMDA ... , 2 types, 4 molecules ACBD

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


Mass: 108085.633 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 / NR2B


Mass: 98845.859 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

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Sugars , 2 types, 5 molecules

#3: Polysaccharide 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 424.401 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1b_1-5_2*NCC/3=O]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][a-D-GlcpNAc]{}}}LINUCSPDB-CARE
#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.: 4
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

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Non-polymers , 2 types, 3 molecules

#5: 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
#6: Chemical ChemComp-QGM / (2R,4S)-5,7-dichloro-4-[(phenylcarbamoyl)amino]-1,2,3,4-tetrahydroquinoline-2-carboxylic acid


Mass: 380.225 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H15Cl2N3O3 / Feature type: SUBJECT OF INVESTIGATION

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Details

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 recording
IDImaging-IDElectron dose (e/Å2)Film or detector model
1164.5GATAN K2 SUMMIT (4k x 4k)
2164.5GATAN 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: C1 (asymmetric)
3D reconstructionResolution: 4.05 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 168065 / Symmetry type: POINT

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