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- PDB-6why: GluN1b-GluN2B NMDA receptor in complex with GluN1 antagonist L689... -

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Basic information

Entry
Database: PDB / ID: 6why
TitleGluN1b-GluN2B NMDA receptor in complex with GluN1 antagonist L689,560, 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 / GluN1 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 / regulation of cell communication / auditory behavior ...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 / regulation of cell communication / auditory behavior / positive regulation of Schwann cell migration / sensitization / olfactory learning / response to hydrogen sulfide / response to other organism / dendritic branch / fear response / conditioned taste aversion / response to methylmercury / protein localization to postsynaptic membrane / regulation of ARF protein signal transduction / apical dendrite / regulation of respiratory gaseous exchange / response to manganese ion / transmitter-gated monoatomic ion channel activity / suckling behavior / interleukin-1 receptor binding / positive regulation of inhibitory postsynaptic potential / response to carbohydrate / cellular response to dsRNA / cellular response to lipid / propylene metabolic process / response to glycine / RAF/MAP kinase cascade / negative regulation of dendritic spine maintenance / response to amine / response to growth hormone / heterocyclic compound binding / neurotransmitter receptor complex / Synaptic adhesion-like molecules / response to glycoside / positive regulation of glutamate secretion / regulation of monoatomic cation transmembrane transport / NMDA glutamate receptor activity / voltage-gated monoatomic cation channel activity / NMDA selective glutamate receptor complex / glutamate binding / ligand-gated sodium channel activity / neuromuscular process / regulation of axonogenesis / calcium ion transmembrane import into cytosol / response to morphine / regulation of dendrite morphogenesis / male mating behavior / protein heterotetramerization / regulation of synapse assembly / small molecule binding / glycine binding / receptor clustering / startle response / positive regulation of reactive oxygen species biosynthetic process / parallel fiber to Purkinje cell synapse / regulation of MAPK cascade / behavioral response to pain / monoatomic ion channel complex / regulation of postsynaptic membrane potential / monoatomic cation transmembrane transport / response to electrical stimulus / action potential / extracellularly glutamate-gated ion channel activity / response to magnesium ion / positive regulation of calcium ion transport into cytosol / cellular response to glycine / associative learning / positive regulation of dendritic spine maintenance / Unblocking of NMDA receptors, glutamate binding and activation / regulation of neuronal synaptic plasticity / monoatomic cation transport / glutamate receptor binding / prepulse inhibition / detection of mechanical stimulus involved in sensory perception of pain / social behavior / ligand-gated monoatomic ion channel activity / response to mechanical stimulus / neuron development / multicellular organismal response to stress / long-term memory / phosphatase binding / postsynaptic density, intracellular component / behavioral fear response / response to fungicide / monoatomic cation channel activity / synaptic cleft / calcium ion homeostasis / positive regulation of synaptic transmission, glutamatergic / cellular response to manganese ion / glutamate-gated receptor activity / regulation of long-term synaptic depression / D2 dopamine receptor binding / 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 / 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 / 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: 4.03 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 2.0Jul 29, 2020Group: Advisory / Atomic model ...Advisory / Atomic model / Data collection / Derived calculations / Structure summary
Category: atom_site / chem_comp ...atom_site / chem_comp / em_entity_assembly / entity / pdbx_branch_scheme / pdbx_chem_comp_identifier / pdbx_entity_branch / pdbx_entity_branch_descriptor / pdbx_entity_branch_link / pdbx_entity_branch_list / pdbx_entity_nonpoly / pdbx_nonpoly_scheme / pdbx_struct_assembly_gen / pdbx_validate_close_contact / struct_asym / struct_conn / struct_site / struct_site_gen
Item: _atom_site.B_iso_or_equiv / _atom_site.Cartn_x ..._atom_site.B_iso_or_equiv / _atom_site.Cartn_x / _atom_site.Cartn_y / _atom_site.Cartn_z / _atom_site.auth_asym_id / _atom_site.auth_atom_id / _atom_site.auth_comp_id / _atom_site.auth_seq_id / _atom_site.label_asym_id / _atom_site.label_atom_id / _atom_site.label_comp_id / _atom_site.label_entity_id / _atom_site.type_symbol / _chem_comp.name / _em_entity_assembly.entity_id_list / _pdbx_entity_nonpoly.entity_id / _pdbx_entity_nonpoly.name / _pdbx_struct_assembly_gen.asym_id_list / _pdbx_validate_close_contact.auth_asym_id_1 / _pdbx_validate_close_contact.auth_asym_id_2 / _pdbx_validate_close_contact.auth_seq_id_1 / _pdbx_validate_close_contact.auth_seq_id_2 / _struct_conn.pdbx_role / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 2.1Aug 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 3.0Dec 25, 2024Group: Advisory / Atomic model ...Advisory / Atomic model / Data collection / Database references / Derived calculations / Structure summary
Category: atom_site / chem_comp_atom ...atom_site / chem_comp_atom / chem_comp_bond / database_2 / em_admin / pdbx_entry_details / pdbx_modification_feature / pdbx_nonpoly_scheme / pdbx_validate_close_contact / struct_conn
Item: _atom_site.auth_seq_id / _database_2.pdbx_DOI ..._atom_site.auth_seq_id / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _em_admin.last_update / _pdbx_entry_details.has_protein_modification / _pdbx_nonpoly_scheme.pdb_seq_num

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Structure visualization

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  • EMDB-21680
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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)415,91510
Polymers413,8634
Non-polymers2,0526
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: 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-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)][b-D-GlcpNAc]{}}}LINUCSPDB-CARE
#4: 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.: 2 / Source method: obtained synthetically / Formula: C17H15Cl2N3O3 / Feature type: SUBJECT OF INVESTIGATION
#5: 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
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen 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: 4.03 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 194228 / Symmetry type: POINT

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