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- PDB-5vos: VGSNKGAIIGL from Amyloid Beta determined by MicroED -

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Basic information

Entry
Database: PDB / ID: 5vos
TitleVGSNKGAIIGL from Amyloid Beta determined by MicroED
ComponentsAmyloid beta A4 protein
KeywordsPROTEIN FIBRIL / Amyloid / steric zipper
Function / homologyRIP-mediated NFkB activation via ZBP1 / Beta-amyloid precursor protein C-terminal / The NLRP3 inflammasome / Amyloidogenic glycoprotein, copper-binding domain superfamily / Amyloidogenic glycoprotein, heparin-binding domain superfamily / E2 domain superfamily / Amyloid beta A4 protein / ECM proteoglycans / Amyloidogenic glycoprotein, E2 domain / Proteinase inhibitor I2, Kunitz, conserved site ...RIP-mediated NFkB activation via ZBP1 / Beta-amyloid precursor protein C-terminal / The NLRP3 inflammasome / Amyloidogenic glycoprotein, copper-binding domain superfamily / Amyloidogenic glycoprotein, heparin-binding domain superfamily / E2 domain superfamily / Amyloid beta A4 protein / ECM proteoglycans / Amyloidogenic glycoprotein, E2 domain / Proteinase inhibitor I2, Kunitz, conserved site / Amyloidogenic glycoprotein, intracellular domain, conserved site / Amyloidogenic glycoprotein, extracellular domain conserved site / Amyloidogenic glycoprotein, heparin-binding / Pancreatic trypsin inhibitor Kunitz domain superfamily / Amyloidogenic glycoprotein, amyloid-beta peptide / PH-like domain superfamily / G alpha (q) signalling events / G alpha (i) signalling events / Amyloidogenic glycoprotein, copper-binding / Lysosome Vesicle Biogenesis / Amyloidogenic glycoprotein / Amyloidogenic glycoprotein, extracellular / Pancreatic trypsin inhibitor Kunitz domain / Formyl peptide receptors bind formyl peptides and many other ligands / Advanced glycosylation endproduct receptor signaling / TAK1 activates NFkB by phosphorylation and activation of IKKs complex / Amyloidogenic glycoprotein, amyloid-beta peptide superfamily / Amyloidogenic glycoprotein extracellular domain signature. / Pancreatic trypsin inhibitor (Kunitz) family signature. / Amyloid fiber formation / E2 domain of amyloid precursor protein / Amyloidogenic glycoprotein intracellular domain signature. / Copper-binding of amyloid precursor, CuBD / TRAF6 mediated NF-kB activation / Post-translational protein phosphorylation / beta-amyloid precursor protein C-terminus / Pancreatic trypsin inhibitor (Kunitz) family profile. / Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models / Beta-amyloid peptide (beta-APP) / DEx/H-box helicases activate type I IFN and inflammatory cytokines production / Amyloid A4 N-terminal heparin-binding / Platelet degranulation / Kunitz/Bovine pancreatic trypsin inhibitor domain / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / positive regulation of cellular response to tunicamycin / positive regulation of cellular response to thapsigargin / positive regulation of protein import / positive regulation of G-protein coupled receptor internalization / regulation of acetylcholine-gated cation channel activity / amylin binding / heparan sulfate binding / positive regulation of response to endoplasmic reticulum stress / receptor activator activity / positive regulation of 1-phosphatidylinositol-3-kinase activity / regulation of response to calcium ion / endosome to plasma membrane transport vesicle / acetylcholine receptor activator activity / collateral sprouting in absence of injury / regulation of dendritic spine maintenance / cellular response to norepinephrine stimulus / lipoprotein particle / synaptic growth at neuromuscular junction / positive regulation of oxidative stress-induced neuron death / microglia development / growth cone lamellipodium / negative regulation of mitochondrion organization / mating behavior / regulation of synapse structure or activity / regulation of amyloid fibril formation / protein trimerization / smooth endoplasmic reticulum calcium ion homeostasis / astrocyte projection / regulation of epidermal growth factor-activated receptor activity / cellular process / growth cone filopodium / regulation of spontaneous synaptic transmission / axo-dendritic transport / axon midline choice point recognition / tumor necrosis factor production / astrocyte activation involved in immune response / positive regulation of astrocyte activation / intermediate-density lipoprotein particle / positive regulation of amyloid fibril formation / PTB domain binding / suckling behavior / modulation of excitatory postsynaptic potential / positive regulation of microglial cell activation / go:0030816: / amyloid-beta complex / neuron remodeling / acetylcholine receptor binding / positive regulation of G-protein coupled receptor protein signaling pathway / activation of MAPKKK activity / main axon / positive regulation of amyloid-beta formation / ciliary rootlet / positive regulation of cell activation / high-density lipoprotein particle / lipoprotein metabolic process / peptidase activator activity
Function and homology information
Specimen sourceHomo sapiens (human)
MethodELECTRON CRYSTALLOGRAPHY / electron crystallography / MOLECULAR REPLACEMENT / molecular replacement / cryo EM / 1.42 Å resolution
AuthorsRodriguez, J.A. / Sawaya, M.R. / Cascio, D. / Eisenberg, D.S. / Griner, S.L. / Gonen, T.
CitationJournal: J. Biol. Chem. / Year: 2018
Title: Common fibrillar spines of amyloid-β and human islet amyloid polypeptide revealed by microelectron diffraction and structure-based inhibitors.
Authors: Pascal Krotee / Sarah L Griner / Michael R Sawaya / Duilio Cascio / Jose A Rodriguez / Dan Shi / Stephan Philipp / Kevin Murray / Lorena Saelices / Ji Lee / Paul Seidler / Charles G Glabe / Lin Jiang / Tamir Gonen / David S Eisenberg
Abstract: Amyloid-β (Aβ) and human islet amyloid polypeptide (hIAPP) aggregate to form amyloid fibrils that deposit in tissues and are associated with Alzheimer's disease (AD) and type II diabetes (T2D), ...Amyloid-β (Aβ) and human islet amyloid polypeptide (hIAPP) aggregate to form amyloid fibrils that deposit in tissues and are associated with Alzheimer's disease (AD) and type II diabetes (T2D), respectively. Individuals with T2D have an increased risk of developing AD, and conversely, AD patients have an increased risk of developing T2D. Evidence suggests that this link between AD and T2D might originate from a structural similarity between aggregates of Aβ and hIAPP. Using the cryoEM method microelectron diffraction, we determined the atomic structures of 11-residue segments from both Aβ and hIAPP, termed Aβ(24-34) WT and hIAPP(19-29) S20G, with 64% sequence similarity. We observed a high degree of structural similarity between their backbone atoms (0.96-Å root mean square deviation). Moreover, fibrils of these segments induced amyloid formation through self- and cross-seeding. Furthermore, inhibitors designed for one segment showed cross-efficacy for full-length Aβ and hIAPP and reduced cytotoxicity of both proteins, although by apparently blocking different cytotoxic mechanisms. The similarity of the atomic structures of Aβ(24-34) WT and hIAPP(19-29) S20G offers a molecular model for cross-seeding between Aβ and hIAPP.
Validation Report
SummaryFull reportAbout validation report
DateDeposition: May 3, 2017 / Release: Jan 3, 2018
RevisionDateData content typeGroupCategoryItemProviderType
1.0Jan 3, 2018Structure modelrepositoryInitial release
1.1Jan 10, 2018Structure modelDatabase referencescitation / citation_author_citation.journal_abbrev / _citation.pdbx_database_id_PubMed / _citation.title
1.2Mar 7, 2018Structure modelDatabase referencescitation_citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation.year
1.3Apr 25, 2018Structure modelData collectiondiffrn_source_diffrn_source.source
1.4Jun 6, 2018Structure modelData collection / Refinement descriptionsoftware

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Structure visualization

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Structure viewerMolecule:
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Assembly

Deposited unit
A: Amyloid beta A4 protein


Theoretical massNumber of molelcules
Total (without water)1,0291
Polyers1,0291
Non-polymers00
Water181
1
A: Amyloid beta A4 protein

A: Amyloid beta A4 protein

A: Amyloid beta A4 protein

A: Amyloid beta A4 protein

A: Amyloid beta A4 protein

A: Amyloid beta A4 protein

A: Amyloid beta A4 protein

A: Amyloid beta A4 protein

A: Amyloid beta A4 protein

A: Amyloid beta A4 protein


Theoretical massNumber of molelcules
Total (without water)10,29210
Polyers10,29210
Non-polymers00
Water18010
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation1_565x,y+1,z1
crystal symmetry operation1_575x,y+2,z1
crystal symmetry operation1_545x,y-1,z1
crystal symmetry operation1_535x,y-2,z1
crystal symmetry operation2_658-x+1,y+1/2,-z+31
crystal symmetry operation2_668-x+1,y+3/2,-z+31
crystal symmetry operation2_678-x+1,y+5/2,-z+31
crystal symmetry operation2_648-x+1,y-1/2,-z+31
crystal symmetry operation2_638-x+1,y-3/2,-z+31
Unit cell
γ
α
β
Length a, b, c (Å)18.780, 4.730, 33.470
Angle α, β, γ (deg.)90.000, 100.020, 90.000
Int Tables number4
Space group name H-MP 1 21 1

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Components

#1: Protein/peptide Amyloid beta A4 protein


Mass: 1029.213 Da / Num. of mol.: 1
Fragment: VGSNKGAIIGL peptide (residues 24-34, UNP residues 7-17)
Source: (synth.) Homo sapiens (human) / References: UniProt: L7XCZ9, UniProt: P05067*PLUS
#2: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1 / Formula: H2O / Water

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Experimental details

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Experiment

ExperimentMethod: ELECTRON CRYSTALLOGRAPHY
EM experimentAggregation state: 3D ARRAY / Reconstruction method: electron crystallography

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Sample preparation

ComponentName: Fibrils of Amyloid Beta segment 24-34 / Type: COMPLEX / Entity ID: 1 / Source: NATURAL
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
EM crystal formationInstrument: microcentrifuge tube / Atmosphere: air / Details: shaking / Temperature: 310 kelvins / Time: 2 DAY
Buffer solutionpH: 4
Buffer component
IDConc.NameBuffer ID
125 mMcitric acid1
25 %DMSO1
SpecimenConc.: 7.5 mg/ml / Details: nanocrystals / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid type: Quantifoil
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE
CrystalDensity Matthews: 1.42
Crystal growTemp: 310 K / Method: batch / pH: 4 / Details: 50 mM sodium citrate, pH 4.0, 10% v/v DMSO

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Data collection

Experimental equipment
Model: Tecnai F20 / Image courtesy: FEI Company
MicroscopyMicroscope model: FEI TECNAI F20
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM
Electron lensMode: DIFFRACTION
Specimen holderCryogen: NITROGEN
Specimen holder model: GATAN 626 SINGLE TILT LIQUID NITROGEN CRYO TRANSFER HOLDER
Image recordingElectron dose: 0.03 e/Å2 / Film or detector model: TVIPS TEMCAM-F416 (4k x 4k) / Number of diffraction images: 471
Image scansWidth: 2048 / Height: 2048
EM diffractionCamera length: 1840 mm
EM diffraction shellFourier space coverage: 47.5 / High resolution: 1.42 Å / Low resolution: 1.49 Å / Multiplicity: 2.6 / Number of structure factors: 84 / Phase residual: 0.01 deg.
EM diffraction statsFourier space coverage: 85.5 / High resolution: 1.42 Å / Number of intensities measured: 5843 / Number of structure factors: 1129 / Overall phase error: 0 deg. / Overall phase residual: 0.01 deg. / Phase error rejection criteria: 0 / R merge: 0.222 / R sym: 0.222
DiffractionMean temperature: 100 kelvins
SourceSource: ELECTRON MICROSCOPE / Type: TECNAI F20 TEM / Wavelength: 0.0251
DetectorType: TVIPS F416 CMOS CAMERA / Detector: CMOS DETECTOR / Collection date: Apr 17, 2015
Radiation wavelengthWavelength: 0.0251 Å / Relative weight: 1
ReflectionB iso Wilson estimate: 14.635 Å2 / D resolution high: 1.42 Å / D resolution low: 32.96 Å / Number obs: 1129 / Observed criterion sigma I: -3 / CC half: 0.98 / Rmerge I obs: 0.222 / Rrim I all: 0.244 / Chi squared: 0.926 / NetI over sigmaI: 4.88 / Number measured all: 5843 / Redundancy: 5.175 % / Scaling rejects: 33 / Percent possible obs: 85.5
Reflection shell

Diffraction ID: 1

Rmerge I obsHighest resolutionLowest resolutionMeanI over sigI obsNumber measured obsNumber possibleNumber unique obsCC halfRrim I allRedundancyPercent possible all
0.4961.4201.4901.090216177840.4520.6112.57147.500
0.3151.4901.5703.1005621811360.8990.3544.13275.100
0.3881.5701.6702.2403801301060.8550.4433.58581.500
0.4211.6701.7802.6605071331150.6540.4794.40986.500
0.3431.7801.9203.7406981311270.9770.3765.49696.900
0.2641.9202.1105.8308991341330.9770.2856.75999.300
0.2732.1102.3606.6409491311290.9420.2967.35798.500
0.2092.3602.7206.20047486860.9900.2315.512100.000
0.2142.7203.3307.02046986860.9220.2385.453100.000
0.1713.3304.72010.09054489880.9760.1846.18298.900
0.1384.72032.9608.34014542390.9890.1613.71892.900

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationContact authorLocationTypeContact author emailLanguageDate
XSCALEdata scalingWolfgang Kabschhttp://www.mpimf-heidelberg.mpg.de/~kabsch/xds/html_doc/xscale_program.htmlpackage
PHASERphasingRandy J. Readhttp://www-structmed.cimr.cam.ac.uk/phaser/programcimr-phaser[at]lists.cam.ac.uk
REFMACrefinementGarib N. Murshudovhttp://www.ccp4.ac.uk/dist/html/refmac5.htmlprogramgarib[at]ysbl.york.ac.ukFortran_77
PDB_EXTRACT3.22data extractionPDBhttp://sw-tools.pdb.org/apps/PDB_EXTRACT/packagedeposit[at]deposit.rcsb.orgC++July. 13, 2016
XDSdata reduction
EM software
IDNameVersionCategory
1TVIPS TemCam-F416image acquisition
6Cootmodel fitting
8phasermolecular replacement
11XSCALEJun 17, 2015crystallography merging
13Refmac5model refinement
EM 3D crystal entityAngle alpha: 90 deg. / Angle beta: 100.017 deg. / Angle gamma: 90 deg. / Length a: 18.78 Å / Length b: 4.73 Å / Length c: 33.47 Å / Space group name: P 21 / Space group num: 4
CTF correctionType: NONE
3D reconstructionResolution method: DIFFRACTION PATTERN/LAYERLINES / Symmetry type: 3D CRYSTAL
Atomic model buildingRef protocol: OTHER / Ref space: RECIPROCAL / Target criteria: Maximum likelihood
RefineMethod to determine structure: MOLECULAR REPLACEMENT / Correlation coeff Fo to Fc: 0.933 / Correlation coeff Fo to Fc free: 0.881
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
Overall SU B: 2.871 / Overall SU ML: 0.1 / Overall SU R Cruickshank DPI: 0.1152 / R Free selection details: RANDOM / Cross valid method: THROUGHOUT / Sigma F: 0 / Overall ESU R: 0.115 / Overall ESU R Free: 0.122
Solvent computationSolvent ion probe radii: 0.8 Å / Solvent shrinkage radii: 0.8 Å / Solvent vdw probe radii: 1.2 Å
Displacement parametersB iso max: 42.18 Å2 / B iso mean: 13.166 Å2 / B iso min: 4.42 Å2 / Aniso B11: 1.04 Å2 / Aniso B12: - Å2 / Aniso B13: 0.83 Å2 / Aniso B22: -1.3 Å2 / Aniso B23: 0 Å2 / Aniso B33: -0.04 Å2
Least-squares processR factor R free: 0.2924 / R factor R work: 0.2335 / R factor obs: 0.2389 / Highest resolution: 1.42 Å / Lowest resolution: 32.96 Å / Number reflection R free: 113 / Number reflection obs: 1014 / Percent reflection R free: 1 / Percent reflection obs: 85.51
Refine hist #finalHighest resolution: 1.42 Å / Lowest resolution: 32.96 Å / B iso mean solvent: 15.91 / Number residues total: 11
Number of atoms included #finalProtein: 72 / Nucleic acid: 0 / Ligand: 0 / Solvent: 1 / Total: 73
Refine LS restraints
Refine IDTypeDev idealDev ideal targetNumber
ELECTRON CRYSTALLOGRAPHYr_bond_refined_d0.0160.01971
ELECTRON CRYSTALLOGRAPHYr_bond_other_d0.0030.02081
ELECTRON CRYSTALLOGRAPHYr_angle_refined_deg1.8382.04094
ELECTRON CRYSTALLOGRAPHYr_angle_other_deg0.6593.000185
ELECTRON CRYSTALLOGRAPHYr_dihedral_angle_1_deg8.7145.00010
ELECTRON CRYSTALLOGRAPHYr_dihedral_angle_2_deg52.25630.0001
ELECTRON CRYSTALLOGRAPHYr_dihedral_angle_3_deg15.73415.00013
ELECTRON CRYSTALLOGRAPHYr_chiral_restr0.0760.20012
ELECTRON CRYSTALLOGRAPHYr_gen_planes_refined0.0050.02080
ELECTRON CRYSTALLOGRAPHYr_gen_planes_other0.0000.02012
Refine LS shellHighest resolution: 1.422 Å / R factor R free: 0.434 / R factor R free error: 0 / R factor R work: 0.367 / Lowest resolution: 1.459 Å / Number reflection R free: 4 / Number reflection R work: 38 / Number reflection all: 42 / Total number of bins used: 20 / Percent reflection obs: 42

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