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- PDB-6o4j: Amyloid Beta KLVFFAENVGS 16-26 D23N Iowa mutation -

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Basic information

Entry
Database: PDB / ID: 6o4j
TitleAmyloid Beta KLVFFAENVGS 16-26 D23N Iowa mutation
ComponentsAmyloid-beta precursor protein
KeywordsPROTEIN FIBRIL / amyloid
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 / Golgi-associated vesicle / neuron remodeling / Insertion of tail-anchored proteins into the endoplasmic reticulum membrane / : / Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models / presynaptic active zone / nuclear envelope lumen / modulation of excitatory postsynaptic potential / suckling behavior / COPII-coated ER to Golgi transport vesicle / dendrite development / smooth endoplasmic reticulum / regulation of NMDA receptor activity / TRAF6 mediated NF-kB activation / negative regulation of long-term synaptic potentiation / Advanced glycosylation endproduct receptor signaling / neuromuscular process controlling balance / 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 / positive regulation of protein metabolic process / ionotropic glutamate receptor signaling pathway / neuron projection maintenance / positive regulation of glycolytic process / extracellular matrix organization / positive regulation of mitotic cell cycle / response to interleukin-1 / axonogenesis / adult locomotory behavior / trans-Golgi network membrane / dendritic shaft / 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 / microglial cell activation / regulation of long-term neuronal synaptic plasticity / positive regulation of JNK cascade / TAK1-dependent IKK and NF-kappa-B activation / neuromuscular junction / visual learning / serine-type endopeptidase inhibitor activity / recycling endosome / cognition / positive regulation of inflammatory response / positive regulation of interleukin-6 production / neuron cellular homeostasis / Golgi lumen / endocytosis / positive regulation of non-canonical NF-kappaB signal transduction / 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, 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 / Amyloidogenic glycoprotein / 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 precursor protein
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON CRYSTALLOGRAPHY / electron crystallography / MOLECULAR REPLACEMENT / cryo EM / Resolution: 1.402 Å
AuthorsGriner, S.L. / Sawaya, M.R. / Rodriguez, J.A. / Cascio, D. / Gonen, T.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Human Genome Research Institute (NIH/NHGRI)R01 AG029430 United States
CitationJournal: Elife / Year: 2019
Title: Structure-based inhibitors of amyloid beta core suggest a common interface with tau.
Authors: Sarah L Griner / Paul Seidler / Jeannette Bowler / Kevin A Murray / Tianxiao Peter Yang / Shruti Sahay / Michael R Sawaya / Duilio Cascio / Jose A Rodriguez / Stephan Philipp / Justyna Sosna ...Authors: Sarah L Griner / Paul Seidler / Jeannette Bowler / Kevin A Murray / Tianxiao Peter Yang / Shruti Sahay / Michael R Sawaya / Duilio Cascio / Jose A Rodriguez / Stephan Philipp / Justyna Sosna / Charles G Glabe / Tamir Gonen / David S Eisenberg /
Abstract: Alzheimer's disease (AD) pathology is characterized by plaques of amyloid beta (Aβ) and neurofibrillary tangles of tau. Aβ aggregation is thought to occur at early stages of the disease, and ...Alzheimer's disease (AD) pathology is characterized by plaques of amyloid beta (Aβ) and neurofibrillary tangles of tau. Aβ aggregation is thought to occur at early stages of the disease, and ultimately gives way to the formation of tau tangles which track with cognitive decline in humans. Here, we report the crystal structure of an Aβ core segment determined by MicroED and in it, note characteristics of both fibrillar and oligomeric structure. Using this structure, we designed peptide-based inhibitors that reduce Aβ aggregation and toxicity of already-aggregated species. Unexpectedly, we also found that these inhibitors reduce the efficiency of Aβ-mediated tau aggregation, and moreover reduce aggregation and self-seeding of tau fibrils. The ability of these inhibitors to interfere with both Aβ and tau seeds suggests these fibrils share a common epitope, and supports the hypothesis that cross-seeding is one mechanism by which amyloid is linked to tau aggregation and could promote cognitive decline.
History
DepositionFeb 28, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 30, 2019Provider: repository / Type: Initial release
Revision 1.1Dec 18, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.2Oct 11, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / em_3d_fitting_list / pdbx_initial_refinement_model / struct_ncs_dom_lim
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _em_3d_fitting_list.accession_code / _em_3d_fitting_list.initial_refinement_model_id / _em_3d_fitting_list.source_name / _em_3d_fitting_list.type / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id

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Structure visualization

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Structure viewerMolecule:
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Assembly

Deposited unit
A: Amyloid-beta precursor protein
B: Amyloid-beta precursor protein


Theoretical massNumber of molelcules
Total (without water)2,4712
Polymers2,4712
Non-polymers00
Water0
1
A: Amyloid-beta precursor protein
B: Amyloid-beta precursor protein

A: Amyloid-beta precursor protein
B: Amyloid-beta precursor protein

A: Amyloid-beta precursor protein
B: Amyloid-beta precursor protein

A: Amyloid-beta precursor protein
B: Amyloid-beta precursor protein

A: Amyloid-beta precursor protein
B: Amyloid-beta precursor protein

A: Amyloid-beta precursor protein
B: Amyloid-beta precursor protein


Theoretical massNumber of molelcules
Total (without water)14,82512
Polymers14,82512
Non-polymers00
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation1_455x-1,y,z1
crystal symmetry operation1_655x+1,y,z1
crystal symmetry operation1_556x,y,z+11
crystal symmetry operation1_456x-1,y,z+11
crystal symmetry operation1_656x+1,y,z+11
Unit cell
Length a, b, c (Å)11.670, 51.910, 12.760
Angle α, β, γ (deg.)90.000, 114.180, 90.000
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11chain A
21chain B

NCS domain segments:

Component-ID: 1 / Ens-ID: 1 / Beg auth comp-ID: ACE / Beg label comp-ID: ACE / End auth comp-ID: NH2 / End label comp-ID: NH2 / Auth seq-ID: 15 - 27 / Label seq-ID: 1 - 13

Dom-IDSelection detailsAuth asym-IDLabel asym-ID
1chain AAA
2chain BBB

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Components

#1: Protein/peptide Amyloid-beta precursor protein / / APP / ABPP / APPI / Alzheimer disease amyloid protein / Amyloid precursor protein / Amyloid-beta A4 ...APP / ABPP / APPI / Alzheimer disease amyloid protein / Amyloid precursor protein / Amyloid-beta A4 protein / Cerebral vascular amyloid peptide / CVAP / PreA4 / Protease nexin-II / PN-II


Mass: 1235.432 Da / Num. of mol.: 2 / Fragment: UNP residues 687-697 / Mutation: D23N / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: P05067

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Experimental details

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Experiment

ExperimentMethod: ELECTRON CRYSTALLOGRAPHY / Number of used crystals: 1
EM experimentAggregation state: 3D ARRAY / 3D reconstruction method: electron crystallography

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Sample preparation

ComponentName: Fibrils of Amyloid Beta segment 16-26 / Type: COMPLEX / Entity ID: all / Source: NATURAL
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
EM crystal formationInstrument: microcentrifuge tube / Atmosphere: air / Temperature: 310 K / Time: 4 DAY
Buffer solutionpH: 8
Buffer component
IDConc.NameFormulaBuffer-ID
1200 mMmagnesium formateMgCl21
210 %DMSODimethyl sulfoxideC2H6OS1
3100 mMTris BaseC4H11NO31
415 %isopropanolC3H8O1
SpecimenConc.: 7.5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES / Details: nanocrystals
Specimen supportDetails: unspecified
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE
CrystalDensity Matthews: 1.43 Å3/Da
Crystal growMethod: unspecified

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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: 1331
Image scansWidth: 2048 / Height: 2048
EM diffractionCamera length: 1840 mm
EM diffraction shellResolution: 1.4→1.44 Å / Fourier space coverage: 78 % / Multiplicity: 12.1 / Num. of structure factors: 163 / Phase residual: 0.01 °
EM diffraction statsFourier space coverage: 85.4 % / High resolution: 1.4 Å / Num. of intensities measured: 47598 / Num. of structure factors: 2355 / Phase error: 0 ° / Phase residual: 0.01 ° / Phase error rejection criteria: 0 / Rmerge: 0.24 / Rsym: 0.24
Diffraction sourceSource: ELECTRON MICROSCOPE / Wavelength: 1 Å
DetectorDate: Nov 7, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: electron
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.4→11.64 Å / Num. obs: 2355 / % possible obs: 85.4 % / Redundancy: 20.211 % / Biso Wilson estimate: 7.23 Å2 / CC1/2: 0.995 / Rmerge(I) obs: 0.24 / Rrim(I) all: 0.246 / Χ2: 0.886 / Net I/σ(I): 9.06 / Num. measured all: 47598 / Scaling rejects: 15
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
1.4-1.4412.0610.6522.8819662091630.6970.68278
1.44-1.4815.6270.5764.0426412031690.6710.59683.3
1.48-1.5216.3330.4894.8724991691530.7880.50390.5
1.52-1.5719.750.3966.4532391891640.9230.40686.8
1.57-1.6223.0360.4716.4938931941690.930.48187.1
1.62-1.6823.5910.4686.8136331891540.8820.47981.5
1.68-1.7419.2360.3946.8424431441270.8990.40488.2
1.74-1.8124.1470.3738.4134531591430.9560.3889.9
1.81-1.8921.8330.3258.931441701440.9840.33284.7
1.89-1.9821.2880.26211.6626611501250.9870.26983.3
1.98-2.0921.5080.27711.4325811351200.9870.28488.9
2.09-2.22220.25712.8326401381200.9770.26287
2.22-2.3720.9910.26911.6723091291100.9610.27685.3
2.37-2.5622.6250.21713.4423531211040.9930.22186
2.56-2.820.3680.21712.621772102870.9860.22385.3
2.8-3.1322.6160.21714.751945105860.9830.22181.9
3.13-3.6220.7290.17915.48145175700.9940.18393.3
3.62-4.4322.4380.15717.46163890730.9950.1681.1
4.43-6.2720.490.16316.61100457490.9980.16786
6.27-11.6413.320.29811.4433329250.9870.30886.2

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Processing

Software
NameVersionClassificationNB
XDSdata reduction
XSCALEdata scaling
PHENIXrefinement
PDB_EXTRACT3.24data extraction
PHASERphasing
EM software
IDNameCategory
6Cootmodel fitting
13PHENIXmodel refinement
EM 3D crystal entity∠α: 90 ° / ∠β: 114.18 ° / ∠γ: 90 ° / A: 11.67 Å / B: 51.91 Å / C: 12.76 Å / Space group name: p21 / Space group num: 4
CTF correctionType: NONE
3D reconstructionResolution: 1.402 Å / Resolution method: DIFFRACTION PATTERN/LAYERLINES / Symmetry type: 3D CRYSTAL
Atomic model buildingProtocol: OTHER / Space: RECIPROCAL / Target criteria: Maximum likelihood
Atomic model buildingPDB-ID: 2Y2A

2y2a


Accession code: 2Y2A / Source name: PDB / Type: experimental model
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 2Y2A

2y2a


Resolution: 1.402→11.64 Å / SU ML: 0.2 / Cross valid method: THROUGHOUT / σ(F): 1.52 / Phase error: 32.51
RfactorNum. reflection% reflection
Rfree0.2832 236 10.03 %
Rwork0.2368 --
obs0.2419 2354 86.16 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 23.08 Å2 / Biso mean: 9.4646 Å2 / Biso min: 1.47 Å2
Refinement stepCycle: final / Resolution: 1.402→11.64 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms178 0 0 0 178
Num. residues----26
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON CRYSTALLOGRAPHYf_bond_d0.014180
ELECTRON CRYSTALLOGRAPHYf_angle_d1.458240
ELECTRON CRYSTALLOGRAPHYf_chiral_restr0.06726
ELECTRON CRYSTALLOGRAPHYf_plane_restr0.00632
ELECTRON CRYSTALLOGRAPHYf_dihedral_angle_d15.77660
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDNumberRefine-IDRmsType
11A80ELECTRON CRYSTALLOGRAPHY24.96TORSIONAL
12B80ELECTRON CRYSTALLOGRAPHY24.96TORSIONAL
LS refinement shell

Refine-ID: ELECTRON CRYSTALLOGRAPHY / Rfactor Rfree error: 0 / Total num. of bins used: 2

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.4017-1.7650.33341150.28021038115386
1.765-11.64090.26231210.21871080120187

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