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- PDB-7sab: Phencyclidine-bound GluN1a-GluN2B NMDA receptors -

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Basic information

Entry
Database: PDB / ID: 7sab
TitlePhencyclidine-bound GluN1a-GluN2B NMDA receptors
Components
  • Glutamate receptor ionotropic, NMDA 1
  • Glutamate receptor ionotropic, NMDA 2B
KeywordsTRANSPORT PROTEIN / Ligand-gated ion channel / ionotropic glutamate receptor / synaptic protein / voltage-gated ion channel
Function / homology
Function and homology information


cellular response to corticosterone stimulus / cellular response to magnesium starvation / trigeminal motor nucleus development / sensory organ development / sensitization / cellular response to curcumin / auditory behavior / pons maturation / regulation of cAMP/PKA signal transduction / fear response ...cellular response to corticosterone stimulus / cellular response to magnesium starvation / trigeminal motor nucleus development / sensory organ development / sensitization / cellular response to curcumin / auditory behavior / pons maturation / regulation of cAMP/PKA signal transduction / fear response / EPHB-mediated forward signaling / positive regulation of Schwann cell migration / Assembly and cell surface presentation of NMDA receptors / response to carbohydrate / regulation of cell communication / protein localization to postsynaptic membrane / conditioned taste aversion / suckling behavior / positive regulation of mitochondrial calcium ion concentration / olfactory learning / response to hydrogen sulfide / response to other organism / response to methylmercury / dendritic branch / regulation of ARF protein signal transduction / ciliary transition zone / cellular response to dsRNA / response to manganese ion / response to glycoside / apical dendrite / transmitter-gated monoatomic ion channel activity / interleukin-1 receptor binding / cellular response to lipid / regulation of respiratory gaseous exchange / propylene metabolic process / response to glycine / response to growth hormone / neurotransmitter receptor complex / heterocyclic compound binding / positive regulation of inhibitory postsynaptic potential / RAF/MAP kinase cascade / response to amine / negative regulation of dendritic spine maintenance / Synaptic adhesion-like molecules / NMDA glutamate receptor activity / regulation of monoatomic cation transmembrane transport / neuromuscular process / NMDA selective glutamate receptor complex / glutamate binding / regulation of axonogenesis / behavioral fear response / ligand-gated sodium channel activity / startle response / voltage-gated monoatomic cation channel activity / regulation of synapse assembly / positive regulation of glutamate secretion / calcium ion transmembrane import into cytosol / response to morphine / positive regulation of reactive oxygen species biosynthetic process / male mating behavior / protein heterotetramerization / regulation of dendrite morphogenesis / small molecule binding / behavioral response to pain / receptor clustering / glycine binding / positive regulation of calcium ion transport into cytosol / parallel fiber to Purkinje cell synapse / associative learning / hypothalamus development / regulation of neuronal synaptic plasticity / social behavior / response to electrical stimulus / regulation of MAPK cascade / regulation of postsynaptic membrane potential / multicellular organismal response to stress / action potential / extracellularly glutamate-gated ion channel activity / positive regulation of dendritic spine maintenance / monoatomic cation transmembrane transport / detection of mechanical stimulus involved in sensory perception of pain / cellular response to glycine / ciliary tip / response to magnesium ion / Unblocking of NMDA receptors, glutamate binding and activation / response to mechanical stimulus / monoatomic cation transport / calcium ion homeostasis / glutamate receptor binding / prepulse inhibition / phosphatase binding / long-term memory / adult locomotory behavior / regulation of long-term neuronal synaptic plasticity / response to fungicide / postsynaptic density, intracellular component / monoatomic cation channel activity / sensory perception of pain / glutamate-gated receptor activity / cellular response to manganese ion
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 / Ligand-gated ion channel / Ionotropic glutamate receptor, L-glutamate and glycine-binding domain / Ligated ion channel L-glutamate- and glycine-binding site / : ...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
1-(PHENYL-1-CYCLOHEXYL)PIPERIDINE / 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: 4.3 Å
AuthorsChou, T.-H. / 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: Nat Struct Mol Biol / Year: 2022
Title: Structural insights into binding of therapeutic channel blockers in NMDA receptors.
Authors: Tsung-Han Chou / Max Epstein / Kevin Michalski / Eve Fine / Philip C Biggin / Hiro Furukawa /
Abstract: Excitatory signaling mediated by N-methyl-D-aspartate receptor (NMDAR) is critical for brain development and function, as well as for neurological diseases and disorders. Channel blockers of NMDARs ...Excitatory signaling mediated by N-methyl-D-aspartate receptor (NMDAR) is critical for brain development and function, as well as for neurological diseases and disorders. Channel blockers of NMDARs are of medical interest owing to their potential for treating depression, Alzheimer's disease, and epilepsy. However, precise mechanisms underlying binding and channel blockade have remained limited owing to challenges in obtaining high-resolution structures at the binding site within the transmembrane domains. Here, we monitor the binding of three clinically important channel blockers: phencyclidine, ketamine, and memantine in GluN1-2B NMDARs at local resolutions of 2.5-3.5 Å around the binding site using single-particle electron cryo-microscopy, molecular dynamics simulations, and electrophysiology. The channel blockers form different extents of interactions with the pore-lining residues, which control mostly off-speeds but not on-speeds. Our comparative analyses of the three unique NMDAR channel blockers provide a blueprint for developing therapeutic compounds with minimal side effects.
History
DepositionSep 22, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 20, 2022Provider: repository / Type: Initial release
Revision 1.0Jul 20, 2022Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Jul 20, 2022Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Jul 20, 2022Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.0Jul 20, 2022Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Jul 20, 2022Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Nov 20, 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 / _pdbx_entry_details.has_protein_modification
Revision 1.2Jun 4, 2025Group: Data collection / Category: em_admin / em_software / Item: _em_admin.last_update / _em_software.name
Revision 1.1Jun 4, 2025Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Data processing / Experimental summary / Data content type: EM metadata / EM metadata / Category: em_admin / em_software / Data content type: EM metadata / EM metadata / Item: _em_admin.last_update / _em_software.name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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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)391,09215
Polymers388,2304
Non-polymers2,86211
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: 95225.883 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: 98888.945 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: 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.: 2
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam 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
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-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.: 8 / Source method: obtained synthetically / 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
#5: Chemical ChemComp-1PC / 1-(PHENYL-1-CYCLOHEXYL)PIPERIDINE / PHENCYCLIDINE


Mass: 243.387 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H25N / Feature type: SUBJECT OF INVESTIGATION
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: Hetero-tetrameric GluN1a-GluN2B NMDAR receptors / 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
Specimen supportGrid material: GOLD / Grid type: UltrAuFoil R1.2/1.3
VitrificationCryogen name: ETHANE / Humidity: 85 % / Chamber temperature: 285 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: 63 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.19.1_4122: / Classification: refinement
EM softwareName: PHENIX / Category: model refinement
CTF correctionType: NONE
3D reconstructionResolution: 4.3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 163971 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00324080
ELECTRON MICROSCOPYf_angle_d0.63832906
ELECTRON MICROSCOPYf_dihedral_angle_d5.1563403
ELECTRON MICROSCOPYf_chiral_restr0.0453912
ELECTRON MICROSCOPYf_plane_restr0.0054194

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