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- PDB-6mmr: Diheteromeric NMDA receptor GluN1/GluN2A in the '2-Knuckle-Symmet... -

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Basic information

Entry
Database: PDB / ID: 6mmr
TitleDiheteromeric NMDA receptor GluN1/GluN2A in the '2-Knuckle-Symmetric' conformation, in complex with glycine and glutamate, in the presence of 1 millimolar zinc chloride, 3 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


response to ammonium ion / regulation of cell communication / directional locomotion / dendritic branch / positive regulation of Schwann cell migration / response to glycine / propylene metabolic process / pons maturation / protein localization to postsynaptic membrane / locomotion ...response to ammonium ion / regulation of cell communication / directional locomotion / dendritic branch / positive regulation of Schwann cell migration / response to glycine / propylene metabolic process / pons maturation / protein localization to postsynaptic membrane / locomotion / response to other organism / serotonin metabolic process / conditioned taste aversion / olfactory learning / cellular response to lipid / regulation of respiratory gaseous exchange / neurotransmitter binding / glutamate-gated calcium ion channel activity / regulation of postsynaptic membrane potential / cellular response to dsRNA / action potential / ligand-gated ion channel activity involved in regulation of presynaptic membrane potential / calcium ion transmembrane import into cytosol / glutamate receptor binding / neuromuscular process / cellular response to zinc ion / dendritic spine organization / response to carbohydrate / voltage-gated cation channel activity / regulation of synapse assembly / NMDA glutamate receptor activity / sleep / NMDA selective glutamate receptor complex / glutamate binding / cellular response to magnesium ion / parallel fiber to Purkinje cell synapse / startle response / glycine binding / neurogenesis / regulation of neuronal synaptic plasticity / response to methylmercury / positive regulation of cysteine-type endopeptidase activity / positive regulation of reactive oxygen species biosynthetic process / dendrite membrane / response to manganese ion / regulation of neuron apoptotic process / cation transport / calcium ion homeostasis / dopamine metabolic process / response to amine / cation channel activity / regulation of dendrite morphogenesis / spinal cord development / positive regulation of calcium ion transport into cytosol / suckling behavior / male mating behavior / regulation of axonogenesis / response to light stimulus / excitatory synapse / social behavior / associative learning / response to morphine / positive regulation of dendritic spine maintenance / long-term memory / response to amphetamine / regulation of NMDA receptor activity / positive regulation of excitatory postsynaptic potential / synaptic cleft / excitatory postsynaptic potential / phosphatase binding / response to cocaine / ionotropic glutamate receptor activity / response to fungicide / integral component of postsynaptic density membrane / calcium channel activity / long-term synaptic potentiation / prepulse inhibition / synaptic membrane / glutamate receptor activity / transmitter-gated ion channel activity involved in regulation of postsynaptic membrane potential / sensory perception of pain / adult locomotory behavior / ionotropic glutamate receptor signaling pathway / visual learning / synaptic transmission, glutamatergic / cellular response to manganese ion / cellular response to amino acid stimulus / regulation of membrane potential / cell adhesion molecule binding / regulation of synaptic plasticity / positive regulation of cell death / cellular calcium ion homeostasis / hippocampal mossy fiber to CA3 synapse / postsynaptic density membrane / protein heterotetramerization / cerebral cortex development / hippocampus development / calcium ion transport / learning / integral component of presynaptic membrane
Ligated ion channel L-glutamate- and glycine-binding site / Ionotropic glutamate receptor / Receptor family ligand binding region / Ligand-gated ion channel / Periplasmic binding protein-like I / Ionotropic glutamate receptor, L-glutamate and glycine-binding domain / Glutamate [NMDA] receptor, epsilon subunit, C-terminal / Calmodulin-binding domain C0, NMDA receptor, NR1 subunit / Receptor, ligand binding region / Ionotropic glutamate receptor, metazoa
Glutamate receptor ionotropic, NMDA 2A / Glutamate receptor ionotropic, NMDA 1
Biological speciesRattus norvegicus (Norway rat)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 5.13 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.
Validation Report
SummaryFull reportAbout validation report
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

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Structure visualization

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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)383,38138
Polymers375,8604
Non-polymers7,52134
Water0
1


TypeNameSymmetry operationNumber
identity operation1_5551
Buried area33290 Å2
ΔGint-79 kcal/mol
Surface area153610 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: 93740.352 Da / Num. of mol.: 2 / Fragment: UNP residues 1-837
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: Sugar...
ChemComp-NAG / N-ACETYL-D-GLUCOSAMINE / N-Acetylglucosamine


Mass: 221.208 Da / Num. of mol.: 34
Source method: isolated from a genetically manipulated source
Formula: C8H15NO6

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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: Diheteromeric NMDA receptor GluN1/GluN2A in the '2-Knuckle-Symmetric' conformation, in complex with glycine and glutamate, in the presence of 1 millimolar zinc chloride, 3 millimolar EDTA, and at pH 7.4
Type: COMPLEX
Details: Sample was heterologously expressed in TSA-201 cells, detergent solubilized, and affinity purified
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 ChlorideNaClSodium chloride1
220 mMHEPESC8H18N2O4S1
31 mg/mLDigitoninC56H92O291
41 mMZinc ChlorideZnCl21
53 mMEDTAEthylenediaminetetraacetic acidC10H16N2O81
SpecimenConc.: 4 mg/ml / Details: This sample was monodisperse / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
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 FIELDBright-field microscopy / 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: 714

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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: 5.13 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 47313 / Algorithm: FOURIER SPACE / Symmetry type: POINT
Atomic model buildingProtocol: RIGID BODY FIT
Atomic model building
IDPDB-IDPdb chain-ID3D fitting-IDPdb chain residue range
14PE5A125-830
25TQ0B134-388
35I57A13-288
45UOWB125-832

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