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- PDB-7sac: S-(+)-ketamine bound GluN1a-GluN2B NMDA receptors at 3.69 Angstro... -

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Basic information

Entry
Database: PDB / ID: 7sac
TitleS-(+)-ketamine bound GluN1a-GluN2B NMDA receptors at 3.69 Angstrom resolution
Components(Glutamate receptor ionotropic, NMDA ...) x 2
KeywordsTRANSPORT PROTEIN / Ligand-gated ion channel / ionotropic glutamate receptor / synaptic protein / voltage-gate ion channel
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 / EPHB-mediated forward signaling / sensitization / auditory behavior ...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 / EPHB-mediated forward signaling / sensitization / auditory behavior / Assembly and cell surface presentation of NMDA receptors / response to hydrogen sulfide / 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 / transmitter-gated monoatomic ion channel activity / fear response / apical dendrite / 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 / cellular response to dsRNA / negative regulation of dendritic spine maintenance / cellular response to lipid / response to growth hormone / regulation of monoatomic cation transmembrane transport / heterocyclic compound binding / NMDA glutamate receptor activity / positive regulation of glutamate secretion / Synaptic adhesion-like molecules / RAF/MAP kinase cascade / voltage-gated monoatomic cation channel activity / response to glycoside / NMDA selective glutamate receptor complex / neurotransmitter receptor complex / ligand-gated sodium channel activity / glutamate binding / 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 / receptor clustering / parallel fiber to Purkinje cell synapse / small molecule binding / regulation of cAMP/PKA signal transduction / 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 / response to magnesium ion / regulation of postsynaptic membrane potential / regulation of neuron apoptotic process / regulation of MAPK cascade / action potential / associative learning / cellular response to glycine / extracellularly glutamate-gated ion channel activity / monoatomic cation transport / excitatory synapse / social behavior / positive regulation of dendritic spine maintenance / response to electrical stimulus / regulation of neuronal synaptic plasticity / monoatomic ion channel complex / positive regulation of excitatory postsynaptic potential / glutamate receptor binding / 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 / positive regulation of synaptic transmission, glutamatergic / behavioral fear response / synaptic cleft / multicellular organismal response to stress / neuron development / prepulse inhibition / postsynaptic density, intracellular component / phosphatase binding / 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
GLUTAMIC ACID / GLYCINE / Chem-JC9 / 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: 3.69 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 1.0Jul 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 1.1Oct 26, 2022Group: Structure summary / Category: chem_comp / Item: _chem_comp.pdbx_synonyms
Revision 1.2Oct 9, 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 1.3May 21, 2025Group: Data collection / Category: em_admin / em_software / Item: _em_admin.last_update / _em_software.name
Revision 1.1May 21, 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)391,73319
Polymers388,2304
Non-polymers3,50415
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: 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

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Sugars , 2 types, 10 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.: 3
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.: 7 / 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

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Non-polymers , 3 types, 5 molecules

#5: Chemical ChemComp-GLY / GLYCINE


Type: peptide linking / Mass: 75.067 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H5NO2 / Feature type: SUBJECT OF INVESTIGATION
#6: Chemical ChemComp-GLU / GLUTAMIC ACID


Type: L-peptide linking / Mass: 147.129 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C5H9NO4 / Feature type: SUBJECT OF INVESTIGATION
#7: Chemical ChemComp-JC9 / (2~{S})-2-(2-chlorophenyl)-2-(methylamino)cyclohexan-1-one / Esketamine


Mass: 237.725 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C13H16ClNO / Feature type: SUBJECT OF INVESTIGATION / Comment: antidepressant*YM

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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: Hetero-tetrameric GluN1a-GluN2B NMDA 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
SpecimenConc.: 4 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen 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: 57.6 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 software
IDNameVersionCategory
8PHENIXmodel refinement
13cisTEM1.0.23D reconstruction
CTF correctionType: NONE
3D reconstructionResolution: 3.69 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 434625 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00323954
ELECTRON MICROSCOPYf_angle_d0.58532694
ELECTRON MICROSCOPYf_dihedral_angle_d6.1293414
ELECTRON MICROSCOPYf_chiral_restr0.0423918
ELECTRON MICROSCOPYf_plane_restr0.0064139

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