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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 / homology
Function and homology information


regulation of epidermal growth factor-activated receptor activity / signaling receptor activator activity / cytosolic mRNA polyadenylation / collateral sprouting in absence of injury / microglia development / regulation of synapse structure or activity / Formyl peptide receptors bind formyl peptides and many other ligands / axo-dendritic transport / synaptic assembly at neuromuscular junction / smooth endoplasmic reticulum calcium ion homeostasis ...regulation of epidermal growth factor-activated receptor activity / signaling receptor activator activity / cytosolic mRNA polyadenylation / collateral sprouting in absence of injury / microglia development / regulation of synapse structure or activity / Formyl peptide receptors bind formyl peptides and many other ligands / axo-dendritic transport / synaptic assembly at neuromuscular junction / smooth endoplasmic reticulum calcium ion homeostasis / axon midline choice point recognition / astrocyte activation involved in immune response / regulation of spontaneous synaptic transmission / regulation of Wnt signaling pathway / mating behavior / positive regulation of amyloid fibril formation / ciliary rootlet / Lysosome Vesicle Biogenesis / PTB domain binding / neuron remodeling / Golgi-associated vesicle / Insertion of tail-anchored proteins into the endoplasmic reticulum membrane / presynaptic active zone / Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models / : / nuclear envelope lumen / COPII-coated ER to Golgi transport vesicle / modulation of excitatory postsynaptic potential / suckling behavior / dendrite development / smooth endoplasmic reticulum / regulation of NMDA receptor activity / TRAF6 mediated NF-kB activation / negative regulation of long-term synaptic potentiation / neuromuscular process controlling balance / Advanced glycosylation endproduct receptor signaling / regulation of presynapse assembly / The NLRP3 inflammasome / intracellular copper ion homeostasis / transition metal ion binding / regulation of multicellular organism growth / negative regulation of neuron differentiation / ECM proteoglycans / spindle midzone / positive regulation of T cell migration / Purinergic signaling in leishmaniasis infection / positive regulation of calcium-mediated signaling / forebrain development / regulation of peptidyl-tyrosine phosphorylation / positive regulation of chemokine production / clathrin-coated pit / Notch signaling pathway / cholesterol metabolic process / positive regulation of G2/M transition of mitotic cell cycle / ionotropic glutamate receptor signaling pathway / positive regulation of protein metabolic process / neuron projection maintenance / positive regulation of glycolytic process / extracellular matrix organization / response to interleukin-1 / axonogenesis / positive regulation of mitotic cell cycle / adult locomotory behavior / dendritic shaft / trans-Golgi network membrane / locomotory behavior / platelet alpha granule lumen / positive regulation of peptidyl-threonine phosphorylation / learning / positive regulation of interleukin-1 beta production / central nervous system development / positive regulation of long-term synaptic potentiation / astrocyte activation / endosome lumen / Post-translational protein phosphorylation / synapse organization / positive regulation of JNK cascade / microglial cell activation / visual learning / regulation of long-term neuronal synaptic plasticity / TAK1-dependent IKK and NF-kappa-B activation / neuromuscular junction / serine-type endopeptidase inhibitor activity / cognition / recycling endosome / positive regulation of inflammatory response / neuron cellular homeostasis / positive regulation of interleukin-6 production / Golgi lumen / positive regulation of non-canonical NF-kappaB signal transduction / endocytosis / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / neuron projection development / cellular response to amyloid-beta / positive regulation of DNA-binding transcription factor activity / G2/M transition of mitotic cell cycle / cell-cell junction / synaptic vesicle / positive regulation of tumor necrosis factor production / regulation of translation
Similarity search - Function
Amyloidogenic glycoprotein, copper-binding / Amyloidogenic glycoprotein, copper-binding domain conserved site / Amyloidogenic glycoprotein, copper-binding domain superfamily / Copper-binding of amyloid precursor, CuBD / Amyloid precursor protein (APP) copper-binding (CuBD) domain signature. / Amyloidogenic glycoprotein, amyloid-beta peptide superfamily / Beta-amyloid peptide (beta-APP) / Amyloidogenic glycoprotein, amyloid-beta peptide / Beta-amyloid precursor protein C-terminal / Amyloidogenic glycoprotein, intracellular domain, conserved site ...Amyloidogenic glycoprotein, copper-binding / Amyloidogenic glycoprotein, copper-binding domain conserved site / Amyloidogenic glycoprotein, copper-binding domain superfamily / Copper-binding of amyloid precursor, CuBD / Amyloid precursor protein (APP) copper-binding (CuBD) domain signature. / Amyloidogenic glycoprotein, amyloid-beta peptide superfamily / Beta-amyloid peptide (beta-APP) / Amyloidogenic glycoprotein, amyloid-beta peptide / Beta-amyloid precursor protein C-terminal / Amyloidogenic glycoprotein, intracellular domain, conserved site / Beta-amyloid precursor protein C-terminus / Amyloid precursor protein (APP) intracellular domain signature. / Amyloid precursor protein (APP) E1 domain profile. / Amyloid precursor protein (APP) E2 domain profile. / Amyloidogenic glycoprotein, extracellular / Amyloidogenic glycoprotein / Amyloidogenic glycoprotein, heparin-binding / Amyloidogenic glycoprotein, E2 domain / E2 domain superfamily / Amyloidogenic glycoprotein, heparin-binding domain superfamily / Amyloid A4 N-terminal heparin-binding / E2 domain of amyloid precursor protein / amyloid A4 / Proteinase inhibitor I2, Kunitz, conserved site / Pancreatic trypsin inhibitor (Kunitz) family signature. / BPTI/Kunitz family of serine protease inhibitors. / Pancreatic trypsin inhibitor Kunitz domain / Kunitz/Bovine pancreatic trypsin inhibitor domain / Pancreatic trypsin inhibitor (Kunitz) family profile. / Pancreatic trypsin inhibitor Kunitz domain superfamily / PH-like domain superfamily
Similarity search - Domain/homology
Amyloid-beta A4 protein / Amyloid-beta precursor protein
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON CRYSTALLOGRAPHY / electron crystallography / MOLECULAR REPLACEMENT / molecular replacement / cryo EM / Resolution: 1.42 Å
AuthorsRodriguez, J.A. / Sawaya, M.R. / Cascio, D. / Eisenberg, D.S. / Griner, S.L. / Gonen, T.
Funding support United States, 1items
OrganizationGrant numberCountry
Howard Hughes Medical Institute (HHMI) United States
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 / ...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.
History
DepositionMay 3, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 3, 2018Provider: repository / Type: Initial release
Revision 1.1Jan 10, 2018Group: Database references / Category: citation / citation_author
Item: _citation.journal_abbrev / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Mar 7, 2018Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation.year
Revision 1.3Apr 25, 2018Group: Data collection / Category: diffrn_source / Item: _diffrn_source.source
Revision 1.4Jun 6, 2018Group: Data collection / Refinement description / Category: software
Revision 1.5Nov 20, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.6Jun 30, 2021Group: Data collection / Category: diffrn_detector / Item: _diffrn_detector.detector
Revision 1.7Mar 13, 2024Group: Data collection / Database references
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / em_author_list
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

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Assembly

Deposited unit
A: Amyloid beta A4 protein


Theoretical massNumber of molelcules
Total (without water)1,0291
Polymers1,0291
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
Polymers10,29210
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
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-MP1211

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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 method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: L7XCZ9, UniProt: P05067*PLUS
#2: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: ELECTRON CRYSTALLOGRAPHY
EM experimentAggregation state: 3D ARRAY / 3D 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 K / Time: 2 DAY
Buffer solutionpH: 4
Buffer component
IDConc.NameBuffer-ID
125 mMcitric acid1
25 %DMSODimethyl sulfoxide1
SpecimenConc.: 7.5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES / Details: nanocrystals
Specimen supportGrid type: Quantifoil
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE
CrystalDensity Matthews: 1.42 Å3/Da
Crystal growTemperature: 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
MicroscopyModel: 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) / Num. of diffraction images: 471
Image scansWidth: 2048 / Height: 2048
EM diffractionCamera length: 1840 mm
EM diffraction shellResolution: 1.42→1.49 Å / Fourier space coverage: 47.5 % / Multiplicity: 2.6 / Num. of structure factors: 84 / Phase residual: 0.01 °
EM diffraction statsFourier space coverage: 85.5 % / High resolution: 1.42 Å / Num. of intensities measured: 5843 / Num. of structure factors: 1129 / Phase error: 0 ° / Phase residual: 0.01 ° / Phase error rejection criteria: 0 / Rmerge: 0.222 / Rsym: 0.222
DiffractionMean temperature: 100 K
Diffraction sourceSource: ELECTRON MICROSCOPE / Type: TECNAI F20 TEM / Wavelength: 0.0251 Å
DetectorType: TVIPS F416 CMOS CAMERA / Detector: CMOS / Date: Apr 17, 2015
Radiation wavelengthWavelength: 0.0251 Å / Relative weight: 1
ReflectionResolution: 1.42→32.96 Å / Num. obs: 1129 / % possible obs: 85.5 % / Observed criterion σ(I): -3 / Redundancy: 5.175 % / Biso Wilson estimate: 14.635 Å2 / CC1/2: 0.98 / Rmerge(I) obs: 0.222 / Rrim(I) all: 0.244 / Χ2: 0.926 / Net I/σ(I): 4.88 / Num. measured all: 5843 / Scaling rejects: 33
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured obsNum. possibleNum. unique obsCC1/2Rrim(I) all% possible all
1.42-1.492.5710.4961.09216177840.4520.61147.5
1.49-1.574.1320.3153.15621811360.8990.35475.1
1.57-1.673.5850.3882.243801301060.8550.44381.5
1.67-1.784.4090.4212.665071331150.6540.47986.5
1.78-1.925.4960.3433.746981311270.9770.37696.9
1.92-2.116.7590.2645.838991341330.9770.28599.3
2.11-2.367.3570.2736.649491311290.9420.29698.5
2.36-2.725.5120.2096.247486860.990.231100
2.72-3.335.4530.2147.0246986860.9220.238100
3.33-4.726.1820.17110.0954489880.9760.18498.9
4.72-32.963.7180.1388.3414542390.9890.16192.9

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
XSCALEdata scaling
PHASERphasing
REFMACrefinement
PDB_EXTRACT3.22data extraction
XDSdata reduction
EM software
IDNameVersionCategory
1TVIPS TemCam-F416image acquisition
6Cootmodel fitting
8phasermolecular replacement
11XSCALEJun 17, 2015crystallography merging
13Refmac5model refinement
EM 3D crystal entity∠α: 90 ° / ∠β: 100.017 ° / ∠γ: 90 ° / A: 18.78 Å / B: 4.73 Å / C: 33.47 Å / Space group name: P21 / Space group num: 4
CTF correctionType: NONE
3D reconstructionResolution method: DIFFRACTION PATTERN/LAYERLINES / Symmetry type: 3D CRYSTAL
Atomic model buildingProtocol: OTHER / Space: RECIPROCAL / Target criteria: Maximum likelihood
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.42→32.96 Å / Cor.coef. Fo:Fc: 0.933 / Cor.coef. Fo:Fc free: 0.881 / SU B: 2.871 / SU ML: 0.1 / SU R Cruickshank DPI: 0.1152 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.115 / ESU R Free: 0.122
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2924 113 10 %RANDOM
Rwork0.2335 ---
obs0.2389 1014 85.51 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 42.18 Å2 / Biso mean: 13.166 Å2 / Biso min: 4.42 Å2
Baniso -1Baniso -2Baniso -3
1-1.04 Å2-0 Å20.83 Å2
2---1.3 Å20 Å2
3----0.04 Å2
Refinement stepCycle: final / Resolution: 1.42→32.96 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms72 0 0 1 73
Biso mean---15.91 -
Num. residues----11
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
ELECTRON CRYSTALLOGRAPHYr_bond_refined_d0.0160.01971
ELECTRON CRYSTALLOGRAPHYr_bond_other_d0.0030.0281
ELECTRON CRYSTALLOGRAPHYr_angle_refined_deg1.8382.0494
ELECTRON CRYSTALLOGRAPHYr_angle_other_deg0.6593185
ELECTRON CRYSTALLOGRAPHYr_dihedral_angle_1_deg8.714510
ELECTRON CRYSTALLOGRAPHYr_dihedral_angle_2_deg52.256301
ELECTRON CRYSTALLOGRAPHYr_dihedral_angle_3_deg15.7341513
ELECTRON CRYSTALLOGRAPHYr_chiral_restr0.0760.212
ELECTRON CRYSTALLOGRAPHYr_gen_planes_refined0.0050.0280
ELECTRON CRYSTALLOGRAPHYr_gen_planes_other00.0212
LS refinement shellResolution: 1.422→1.459 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.434 4 -
Rwork0.367 38 -
all-42 -
obs--42 %

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