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- PDB-6mmv: Triheteromeric NMDA receptor GluN1/GluN2A/GluN2A* Extracellular D... -

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Basic information

Entry
Database: PDB / ID: 6mmv
TitleTriheteromeric NMDA receptor GluN1/GluN2A/GluN2A* Extracellular Domain in the '2-Knuckle-Asymmetric' conformation, in complex with glycine and glutamate, in the presence of 1 micromolar zinc chloride, and at pH 7.4
Components
  • (Glutamate receptor ionotropic, NMDA 2A) x 2
  • Glutamate receptor ionotropic, NMDA 1
KeywordsTRANSPORT PROTEIN / Ligand-gated Ion Channel / NMDA Receptor / ionotropic Glutamate Receptors / membrane protein
Function / homologyEPHB-mediated forward signaling / Unblocking of NMDA receptors, glutamate binding and activation / Ligated ion channel L-glutamate- and glycine-binding site / Ligand-gated ion channel / Glutamate [NMDA] receptor, epsilon subunit, C-terminal / Receptor, ligand binding region / Receptor family ligand binding region / Periplasmic binding protein-like I / N-methyl D-aspartate receptor 2B3 C-terminus / Calmodulin-binding domain C0 of NMDA receptor NR1 subunit ...EPHB-mediated forward signaling / Unblocking of NMDA receptors, glutamate binding and activation / Ligated ion channel L-glutamate- and glycine-binding site / Ligand-gated ion channel / Glutamate [NMDA] receptor, epsilon subunit, C-terminal / Receptor, ligand binding region / Receptor family ligand binding region / Periplasmic binding protein-like I / N-methyl D-aspartate receptor 2B3 C-terminus / Calmodulin-binding domain C0 of NMDA receptor NR1 subunit / Ionotropic glutamate receptor / Ionotropic glutamate receptor, L-glutamate and glycine-binding domain / CREB phosphorylation through the activation of CaMKII / Ras activation upon Ca2+ influx through NMDA receptor / RAF/MAP kinase cascade / Synaptic adhesion-like molecules / Calmodulin-binding domain C0, NMDA receptor, NR1 subunit / Ionotropic glutamate receptor, metazoa / response to ammonium ion / dendritic branch / response to other organism / calcium ion transmembrane import into cytosol / cellular response to lipid / glutamate-gated calcium ion channel activity / neurotransmitter binding / ligand-gated ion channel activity involved in regulation of presynaptic membrane potential / parallel fiber to Purkinje cell synapse / action potential / cellular response to dsRNA / response to carbohydrate / glutamate receptor binding / voltage-gated cation channel activity / glycine binding / cellular response to zinc ion / NMDA glutamate receptor activity / cellular response to magnesium ion / glutamate binding / NMDA selective glutamate receptor complex / dendrite membrane / synaptic membrane / positive regulation of cysteine-type endopeptidase activity / response to methylmercury / postsynaptic density membrane / positive regulation of reactive oxygen species biosynthetic process / response to manganese ion / response to amine / spinal cord development / positive regulation of calcium ion transport into cytosol / response to light stimulus / excitatory synapse / excitatory postsynaptic potential / synaptic cleft / transmitter-gated ion channel activity involved in regulation of postsynaptic membrane potential / positive regulation of dendritic spine maintenance / response to cocaine / positive regulation of excitatory postsynaptic potential / phosphatase binding / integral component of postsynaptic density membrane / cerebral cortex development / response to fungicide / long-term synaptic potentiation / ionotropic glutamate receptor activity / cellular response to growth factor stimulus / ionotropic glutamate receptor signaling pathway / hippocampus development / cell adhesion molecule binding / cellular response to amino acid stimulus / cellular response to manganese ion / hippocampal mossy fiber to CA3 synapse / positive regulation of cell death / integral component of presynaptic membrane / regulation of long-term neuronal synaptic plasticity / memory / terminal bouton / presynaptic membrane / rhythmic process / protein heterotetramerization / response to calcium ion / response to organic cyclic compound / learning or memory / protein tetramerization / chemical synaptic transmission / scaffold protein binding / ATPase binding / response to ethanol / dendritic spine / postsynaptic density / protein dimerization activity / protein-containing complex binding / neuron projection / cell junction / synapse / response to drug / glutamatergic synapse / intracellular / neuronal cell body / signaling receptor binding / protein heterodimerization activity / protein kinase binding / integral component of plasma membrane
Function and homology information
Specimen sourceRattus norvegicus (Norway rat)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / 4.71 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: Oct 1, 2018 / Release: Nov 28, 2018

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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)367,23742
Polyers358,8314
Non-polymers8,40638
Water0
1


TypeNameSymmetry operationNumber
identity operation1_5551
Buried area (Å2)21290
ΔGint (kcal/M)53
Surface area (Å2)126500

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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: 89853.656 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: 89580.523 Da / Num. of mol.: 1 / Fragment: UNP residues 1-800 / 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: Protein/peptide Glutamate receptor ionotropic, NMDA 2A / GluN2A / Glutamate [NMDA] receptor subunit epsilon-1 / N-methyl D-aspartate receptor subtype 2A / NR2A


Mass: 89543.477 Da / Num. of mol.: 1 / Fragment: UNP residues 1-800 / Mutation: H128S, N687Q / 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
#4: Chemical...
ChemComp-NAG / N-ACETYL-D-GLUCOSAMINE


Mass: 221.208 Da / Num. of mol.: 38 / 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: Triheteromeric NMDA receptor GluN1/GluN2A/GluN2A* Extracellular Domain in the '2-Knuckle-Asymmetric' conformation, in complex with glycine and glutamate, in the presence of 1 micromolar zinc chloride, 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, 3 / 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: 7.4
Buffer component
IDConc.NameFormulaBuffer ID
1150 mMSodium ChlorideNaCl1
220 mMHEPESC8H18N2O4S1
31 mg/mLDigitoninC56H92O291
41 uMZinc ChlorideZnCl21
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 / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 291 kelvins / 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 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) / Number of grids imaged: 1 / Number of real images: 1891

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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: 4.71 Å / Resolution method: FSC 0.143 CUT-OFF / Number of particles: 68275 / 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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