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- PDB-6mmb: Diheteromeric NMDA receptor GluN1/GluN2A in the 'Super-Splayed' c... -

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Basic information

Entry
Database: PDB / ID: 6mmb
TitleDiheteromeric NMDA receptor GluN1/GluN2A in the 'Super-Splayed' conformation, in complex with glycine and glutamate, in the presence of 1 micromolar zinc chloride, and at pH 6.1
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 / homologyEPHB-mediated forward signaling / Receptor family ligand binding region / Receptor, ligand binding region / Glutamate [NMDA] receptor, epsilon subunit, C-terminal / Ionotropic glutamate receptor, metazoa / Ionotropic glutamate receptor / Ligand-gated ion channel / Calmodulin-binding domain C0, NMDA receptor, NR1 subunit / Unblocking of NMDA receptors, glutamate binding and activation / Periplasmic binding protein-like I ...EPHB-mediated forward signaling / Receptor family ligand binding region / Receptor, ligand binding region / Glutamate [NMDA] receptor, epsilon subunit, C-terminal / Ionotropic glutamate receptor, metazoa / Ionotropic glutamate receptor / Ligand-gated ion channel / Calmodulin-binding domain C0, NMDA receptor, NR1 subunit / Unblocking of NMDA receptors, glutamate binding and activation / Periplasmic binding protein-like I / N-methyl D-aspartate receptor 2B3 C-terminus / CREB1 phosphorylation through the activation of CaMKII/CaMKK/CaMKIV cascasde / rt:r-rno-442982: / RAF/MAP kinase cascade / Synaptic adhesion-like molecules / Ionotropic glutamate receptor, L-glutamate and glycine-binding domain / Calmodulin-binding domain C0 of NMDA receptor NR1 subunit / Ligated ion channel L-glutamate- and glycine-binding site / response to ammonium ion / dendritic branch / positive regulation of Schwann cell migration / response to other organism / cellular response to lipid / ligand-gated ion channel activity involved in regulation of presynaptic membrane potential / glutamate-gated calcium ion channel activity / cellular response to dsRNA / neurotransmitter binding / calcium ion transmembrane import into cytosol / action potential / glutamate receptor binding / voltage-gated cation channel activity / cellular response to zinc ion / glycine binding / parallel fiber to Purkinje cell synapse / response to carbohydrate / cellular response to magnesium ion / NMDA glutamate receptor activity / glutamate binding / NMDA selective glutamate receptor complex / synaptic membrane / dendrite membrane / response to methylmercury / positive regulation of cysteine-type endopeptidase activity / positive regulation of reactive oxygen species biosynthetic process / response to manganese ion / spinal cord development / postsynaptic density membrane / response to amine / positive regulation of calcium ion transport into cytosol / response to light stimulus / excitatory synapse / excitatory postsynaptic potential / positive regulation of dendritic spine maintenance / synaptic cleft / positive regulation of excitatory postsynaptic potential / phosphatase binding / response to cocaine / response to fungicide / integral component of postsynaptic density membrane / cerebral cortex development / transmitter-gated ion channel activity involved in regulation of postsynaptic membrane potential / ionotropic glutamate receptor activity / cellular response to growth factor stimulus / long-term synaptic potentiation / ionotropic glutamate receptor signaling pathway / cellular response to amino acid stimulus / cell adhesion molecule binding / hippocampus development / cellular response to manganese ion / positive regulation of cell death / hippocampal mossy fiber to CA3 synapse / memory / integral component of presynaptic membrane / regulation of long-term neuronal synaptic plasticity / presynaptic membrane / terminal bouton / rhythmic process / response to calcium ion / response to organic cyclic compound / protein heterotetramerization / learning or memory / protein tetramerization / chemical synaptic transmission / scaffold protein binding / amyloid-beta binding / ATPase binding / response to ethanol / dendritic spine / postsynaptic density / protein dimerization activity / protein-containing complex binding / cell junction / synapse / neuron projection / response to drug / glutamatergic synapse / neuronal cell body / signaling receptor binding / protein heterodimerization activity / protein kinase binding
Function and homology information
Specimen sourceRattus norvegicus (Norway rat)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / 12.7 Å resolution
AuthorsJalali-Yazdi, F. / Chowdhury, S. / Yoshioka, C. / Gouaux, E.
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
DateDeposition: Sep 30, 2018 / Release: Nov 28, 2018
RevisionDateData content typeGroupCategoryItemProviderType
1.0Nov 28, 2018Structure modelrepositoryInitial release
1.1Dec 19, 2018Structure modelData collection / Database referencescitation / citation_author_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

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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
Polyers375,8604
Non-polymers7,52134
Water0
1


TypeNameSymmetry operationNumber
identity operation1_5551
Buried area (Å2)31050
ΔGint (kcal/M)-55
Surface area (Å2)157780

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Components

#1: Protein/peptide 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: (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/peptide 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: (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: Chemical...
ChemComp-NAG / N-ACETYL-D-GLUCOSAMINE


Mass: 221.208 Da / Num. of mol.: 34 / Formula: C8H15NO6 / N-Acetylglucosamine

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / Reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Diheteromeric NMDA receptor GluN1/GluN2A in the 'Super-Splayed' conformation, in complex with glycine and glutamate, in the presence of 1 micromolar zinc chloride, and at pH 6.1
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)Cell: TSA-201 / Organism: Homo sapiens (human)
Buffer solutionpH: 6.1
Buffer component
IDConc.NameFormulaBuffer ID
1150 mMSodium ChlorideNaCl1
220 mMMESC6H13NO4S1
31 mg/mLDigitoninC56H92O291
41 uMZinc ChlorideZnCl21
SpecimenConc.: 4 / 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 / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 291 / 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
MicroscopyMicroscope model: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy / Cs: 2.7
Image recordingAverage exposure time: 22 / Electron dose: 52 / Film or detector model: GATAN K2 BASE (4k x 4k) / Number of grids imaged: 1 / Number of real images: 2163

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Processing

SoftwareName: PHENIX / Version: 1.13_2998: / Classification: refinement
EM software
IDNameCategoryDetails
2SerialEMimage acquisition
4GctfCTF correction
7UCSF Chimeramodel fitting
8PyMOLmodel fitting
10PHENIXmodel refinement
11Cootmodel refinement
12RELIONinitial Euler assignment
13RELIONfinal Euler assignment
14RELIONclassification
15FREALIGN3D reconstructionTechnically, the Frealign implimentation in cisTEM
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C1
3D reconstructionResolution: 12.7 / Resolution method: FSC 0.143 CUT-OFF / Number of particles: 10238 / Algorithm: FOURIER SPACE / Symmetry type: POINT
Atomic model buildingRef protocol: RIGID BODY FIT
Atomic model building
IDPDB-IDPdb chain ID 3D fitting IDPdb chain residue range
14PE5A125-830
25TQ0B134-388
35I57A13-288
45UOWB125-832

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