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- PDB-6mms: Triheteromeric NMDA receptor GluN1/GluN2A/GluN2A* in the '2-Knuck... -

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Basic information

Entry
Database: PDB / ID: 6mms
TitleTriheteromeric NMDA receptor GluN1/GluN2A/GluN2A* in the '2-Knuckle-Symmetric' conformation, in complex with glycine and glutamate, in the presence of 1 millimolar EDTA, and at pH 7.4
Components
  • Glutamate receptor ionotropic, NMDA 1
  • Glutamate receptor ionotropic, NMDA 2A
KeywordsTRANSPORT PROTEIN / Ligand-gated Ion Channel / NMDA Receptor / ionotropic Glutamate Receptors / membrane protein
Function / homology
Function and homology information


regulation of response to alcohol / response to ammonium ion / neurotransmitter receptor transport, plasma membrane to endosome / receptor recycling / response to environmental enrichment / directional locomotion / EPHB-mediated forward signaling / pons maturation / Assembly and cell surface presentation of NMDA receptors / response to hydrogen sulfide ...regulation of response to alcohol / response to ammonium ion / neurotransmitter receptor transport, plasma membrane to endosome / receptor recycling / response to environmental enrichment / directional locomotion / EPHB-mediated forward signaling / pons maturation / Assembly and cell surface presentation of NMDA receptors / response to hydrogen sulfide / regulation of cell communication / auditory behavior / positive regulation of Schwann cell migration / olfactory learning / conditioned taste aversion / response to other organism / cellular response to magnesium ion / dendritic branch / regulation of respiratory gaseous exchange / response to methylmercury / protein localization to postsynaptic membrane / serotonin metabolic process / regulation of ARF protein signal transduction / response to manganese ion / response to carbohydrate / transmitter-gated monoatomic ion channel activity / suckling behavior / positive regulation of inhibitory postsynaptic potential / sleep / cellular response to dsRNA / propylene metabolic process / response to glycine / regulation of NMDA receptor activity / cellular response to lipid / locomotion / dendritic spine organization / RAF/MAP kinase cascade / response to amine / Synaptic adhesion-like molecules / regulation of monoatomic cation transmembrane transport / NMDA glutamate receptor activity / response to glycoside / NMDA selective glutamate receptor complex / voltage-gated monoatomic cation channel activity / glutamate binding / neurotransmitter receptor complex / ligand-gated sodium channel activity / glutamate receptor signaling pathway / regulation of axonogenesis / calcium ion transmembrane import into cytosol / neuromuscular process / response to morphine / regulation of dendrite morphogenesis / protein heterotetramerization / male mating behavior / regulation of synapse assembly / spinal cord development / glycine binding / startle response / cellular response to zinc ion / dopamine metabolic process / positive regulation of reactive oxygen species biosynthetic process / parallel fiber to Purkinje cell synapse / response to lithium ion / monoatomic cation transmembrane transport / monoatomic ion channel complex / cellular response to glycine / positive regulation of calcium ion transport into cytosol / regulation of postsynaptic membrane potential / response to light stimulus / action potential / modulation of excitatory postsynaptic potential / associative learning / positive regulation of dendritic spine maintenance / conditioned place preference / regulation of neuronal synaptic plasticity / monoatomic cation transport / social behavior / positive regulation of protein targeting to membrane / Unblocking of NMDA receptors, glutamate binding and activation / glutamate receptor binding / prepulse inhibition / long-term memory / neuron development / multicellular organismal response to stress / phosphatase binding / positive regulation of synaptic transmission, glutamatergic / postsynaptic density, intracellular component / response to fungicide / monoatomic cation channel activity / synaptic cleft / calcium ion homeostasis / glutamate-gated receptor activity / cellular response to manganese ion / glutamate-gated calcium ion channel activity / neurogenesis / presynaptic active zone membrane / cell adhesion molecule binding / dendrite membrane / excitatory synapse
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
Glutamate receptor ionotropic, NMDA 1 / Glutamate receptor ionotropic, NMDA 2A
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 5.38 Å
AuthorsJalali-Yazdi, F. / Chowdhury, S. / Yoshioka, C. / Gouaux, E.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)R01NS038631 United States
National Institutes of Health/National Institute of Mental Health (NIH/NIMH)1F32MH115595 United States
CitationJournal: Cell / Year: 2018
Title: Mechanisms for Zinc and Proton Inhibition of the GluN1/GluN2A NMDA Receptor.
Authors: Farzad Jalali-Yazdi / Sandipan Chowdhury / Craig Yoshioka / Eric Gouaux /
Abstract: N-methyl-D-aspartate receptors (NMDARs) play essential roles in memory formation, neuronal plasticity, and brain development, with their dysfunction linked to a range of disorders from ischemia to ...N-methyl-D-aspartate receptors (NMDARs) play essential roles in memory formation, neuronal plasticity, and brain development, with their dysfunction linked to a range of disorders from ischemia to schizophrenia. Zinc and pH are physiological allosteric modulators of NMDARs, with GluN2A-containing receptors inhibited by nanomolar concentrations of divalent zinc and by excursions to low pH. Despite the widespread importance of zinc and proton modulation of NMDARs, the molecular mechanism by which these ions modulate receptor activity has proven elusive. Here, we use cryoelectron microscopy to elucidate the structure of the GluN1/GluN2A NMDAR in a large ensemble of conformations under a range of physiologically relevant zinc and proton concentrations. We show how zinc binding to the amino terminal domain elicits structural changes that are transduced though the ligand-binding domain and result in constriction of the ion channel gate.
History
DepositionOct 1, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 28, 2018Provider: repository / Type: Initial release
Revision 1.1Dec 19, 2018Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID
Revision 1.2Nov 27, 2019Group: Author supporting evidence / Data collection / Category: em_software / pdbx_audit_support
Item: _em_software.details / _em_software.name / _pdbx_audit_support.funding_organization
Revision 2.0Jul 29, 2020Group: Atomic model / Data collection ...Atomic model / Data collection / Derived calculations / Structure summary
Category: atom_site / chem_comp ...atom_site / chem_comp / 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 / 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_seq_id / _atom_site.label_asym_id / _atom_site.label_entity_id / _chem_comp.name / _chem_comp.type / _pdbx_entity_nonpoly.entity_id / _pdbx_entity_nonpoly.name / _pdbx_struct_assembly_gen.asym_id_list / _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 2.1Oct 30, 2024Group: Data collection / Database references ...Data collection / Database references / Refinement description / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / em_3d_fitting_list / em_admin / pdbx_entry_details / pdbx_initial_refinement_model / pdbx_modification_feature
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI ..._chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _em_3d_fitting_list.accession_code / _em_3d_fitting_list.initial_refinement_model_id / _em_3d_fitting_list.source_name / _em_3d_fitting_list.type / _em_admin.last_update

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Assembly

Deposited unit
A: Glutamate receptor ionotropic, NMDA 1
B: Glutamate receptor ionotropic, NMDA 2A
C: Glutamate receptor ionotropic, NMDA 1
D: Glutamate receptor ionotropic, NMDA 2A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)383,32836
Polymers375,6404
Non-polymers7,68832
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area31380 Å2
ΔGint-73 kcal/mol
Surface area154490 Å2

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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: 94189.781 Da / Num. of mol.: 2 / Fragment: UNP residues 1-838
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Rattus norvegicus (Norway rat) / Gene: Grin1, Nmdar1 / Variant: 1a / Cell line (production host): TSA-201 / Organ (production host): Kidney / Production host: Homo sapiens (human) / References: UniProt: P35439
#2: Protein Glutamate receptor ionotropic, NMDA 2A / GluN2A / Glutamate [NMDA] receptor subunit epsilon-1 / N-methyl D-aspartate receptor subtype 2A / NR2A


Mass: 93630.258 Da / Num. of mol.: 2 / Fragment: UNP residues 1-837 / Mutation: H128S, N687Q
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Rattus norvegicus (Norway rat) / Gene: Grin2a / Cell line (production host): TSA-201 / Organ (production host): Kidney / Production host: Homo sapiens (human) / References: UniProt: Q00959
#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-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: 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.: 29
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 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: Triheteromeric NMDA receptor GluN1/GluN2A/GluN2A* in the '2-Knuckle-Symmetric' conformation, in complex with glycine and glutamate, in the presence of 1 millimolar EDTA, and at pH 7.4
Type: COMPLEX
Details: Sample was heterologously expressed in TSA-201 cells, detergent solubilized, and affinity purified serially to obtain the triheteromeric receptor
Entity ID: #1-#2 / Source: RECOMBINANT
Molecular weightValue: 0.5 MDa / Experimental value: NO
Source (natural)Organism: Rattus norvegicus (Norway rat)
Source (recombinant)Organism: Homo sapiens (human) / Cell: TSA-201
Buffer solutionpH: 7.4
Buffer component
IDConc.NameFormulaBuffer-ID
1150 mMSodium ChlorideNaCl1
220 mMHEPESC8H18N2O4S1
31 mg/mLDigitoninC56H92O291
41 mMEDTAC10H16N2O81
SpecimenConc.: 4 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES / Details: This sample was monodisperse
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 291 K / Details: Sample was blotted for 3 seconds at blot force 1.

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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 / Cs: 2.7 mm
Image recordingAverage exposure time: 22 sec. / Electron dose: 52 e/Å2 / Film or detector model: GATAN K2 BASE (4k x 4k) / Num. of grids imaged: 1 / Num. of real images: 690

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Processing

SoftwareName: PHENIX / Version: 1.13_2998: / Classification: refinement
EM software
IDNameCategory
2SerialEMimage acquisition
4GctfCTF correction
7UCSF Chimeramodel fitting
8PyMOLmodel fitting
10PHENIXmodel refinement
11Cootmodel refinement
12RELIONinitial Euler assignment
13RELIONfinal Euler assignment
14RELIONclassification
15cisTEM3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 5.38 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 33349 / Algorithm: FOURIER SPACE / Symmetry type: POINT
Atomic model buildingProtocol: RIGID BODY FIT
Atomic model building

3D fitting-ID: 1 / Source name: PDB / Type: experimental model

IDPDB-IDPdb chain-IDAccession codeInitial refinement model-IDPdb chain residue range
14PE5

4pe5

A4PE5125-830
25TQ0

5tq0

B5TQ0234-388
35I57

5i57

A5I5733-288
45UOW

5uow

B5UOW425-832

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