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- PDB-4znn: MicroED structure of the segment, GVVHGVTTVA, from the A53T famil... -

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Entry
Database: PDB / ID: 4znn
TitleMicroED structure of the segment, GVVHGVTTVA, from the A53T familial mutant of Parkinson's disease protein, alpha-synuclein residues 47-56
ComponentsAlpha-synuclein
KeywordsLIPID BINDING PROTEIN / Amyloid / alpha-synuclein / Parkinson's Disease / Toxic Core / NACore
Function / homology
Function and homology information


negative regulation of mitochondrial electron transport, NADH to ubiquinone / : / neutral lipid metabolic process / regulation of acyl-CoA biosynthetic process / negative regulation of dopamine uptake involved in synaptic transmission / negative regulation of norepinephrine uptake / positive regulation of SNARE complex assembly / positive regulation of hydrogen peroxide catabolic process / supramolecular fiber / mitochondrial membrane organization ...negative regulation of mitochondrial electron transport, NADH to ubiquinone / : / neutral lipid metabolic process / regulation of acyl-CoA biosynthetic process / negative regulation of dopamine uptake involved in synaptic transmission / negative regulation of norepinephrine uptake / positive regulation of SNARE complex assembly / positive regulation of hydrogen peroxide catabolic process / supramolecular fiber / mitochondrial membrane organization / negative regulation of chaperone-mediated autophagy / regulation of synaptic vesicle recycling / regulation of reactive oxygen species biosynthetic process / negative regulation of platelet-derived growth factor receptor signaling pathway / positive regulation of protein localization to cell periphery / negative regulation of exocytosis / regulation of glutamate secretion / response to iron(II) ion / SNARE complex assembly / positive regulation of neurotransmitter secretion / dopamine biosynthetic process / regulation of norepinephrine uptake / transporter regulator activity / regulation of locomotion / synaptic vesicle priming / mitochondrial ATP synthesis coupled electron transport / regulation of macrophage activation / positive regulation of inositol phosphate biosynthetic process / negative regulation of microtubule polymerization / synaptic vesicle transport / positive regulation of receptor recycling / dopamine uptake involved in synaptic transmission / protein kinase inhibitor activity / dynein complex binding / regulation of dopamine secretion / negative regulation of thrombin-activated receptor signaling pathway / cuprous ion binding / positive regulation of endocytosis / positive regulation of exocytosis / response to magnesium ion / synaptic vesicle exocytosis / enzyme inhibitor activity / kinesin binding / synaptic vesicle endocytosis / response to type II interferon / regulation of presynapse assembly / cysteine-type endopeptidase inhibitor activity / negative regulation of serotonin uptake / alpha-tubulin binding / supramolecular fiber organization / inclusion body / phospholipid metabolic process / cellular response to copper ion / axon terminus / cellular response to epinephrine stimulus / Hsp70 protein binding / response to interleukin-1 / regulation of microtubule cytoskeleton organization / SNARE binding / positive regulation of release of sequestered calcium ion into cytosol / adult locomotory behavior / negative regulation of protein kinase activity / excitatory postsynaptic potential / fatty acid metabolic process / phosphoprotein binding / protein tetramerization / microglial cell activation / regulation of long-term neuronal synaptic plasticity / synapse organization / ferrous iron binding / protein destabilization / PKR-mediated signaling / phospholipid binding / receptor internalization / tau protein binding / long-term synaptic potentiation / synaptic vesicle membrane / positive regulation of inflammatory response / actin cytoskeleton / actin binding / growth cone / cell cortex / cellular response to oxidative stress / neuron apoptotic process / chemical synaptic transmission / molecular adaptor activity / negative regulation of neuron apoptotic process / response to lipopolysaccharide / histone binding / amyloid fibril formation / lysosome / oxidoreductase activity / postsynapse / transcription cis-regulatory region binding / positive regulation of apoptotic process / copper ion binding / Amyloid fiber formation / response to xenobiotic stimulus / axon / neuronal cell body
Similarity search - Function
Synuclein / Alpha-synuclein / Synuclein
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
MethodELECTRON CRYSTALLOGRAPHY / electron crystallography / MOLECULAR REPLACEMENT / molecular replacement / cryo EM / Resolution: 1.41 Å
AuthorsRodriguez, J.A. / Ivanova, M. / Sawaya, M.R. / Cascio, D. / Reyes, F. / Shi, D. / Johnson, L. / Guenther, E. / Sangwan, S. / Hattne, J. ...Rodriguez, J.A. / Ivanova, M. / Sawaya, M.R. / Cascio, D. / Reyes, F. / Shi, D. / Johnson, L. / Guenther, E. / Sangwan, S. / Hattne, J. / Nannenga, B. / Brewster, A.S. / Messerschmidt, M. / Boutet, S. / Sauter, N.K. / Gonen, T. / Eisenberg, D.S.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute on Aging (NIH/NIA)1R01-AG029430 United States
National Institutes of Health/National Institute on Aging (NIH/NIA)AG016570 United States
CitationJournal: Nature / Year: 2015
Title: Structure of the toxic core of α-synuclein from invisible crystals.
Authors: Jose A Rodriguez / Magdalena I Ivanova / Michael R Sawaya / Duilio Cascio / Francis E Reyes / Dan Shi / Smriti Sangwan / Elizabeth L Guenther / Lisa M Johnson / Meng Zhang / Lin Jiang / Mark ...Authors: Jose A Rodriguez / Magdalena I Ivanova / Michael R Sawaya / Duilio Cascio / Francis E Reyes / Dan Shi / Smriti Sangwan / Elizabeth L Guenther / Lisa M Johnson / Meng Zhang / Lin Jiang / Mark A Arbing / Brent L Nannenga / Johan Hattne / Julian Whitelegge / Aaron S Brewster / Marc Messerschmidt / Sébastien Boutet / Nicholas K Sauter / Tamir Gonen / David S Eisenberg /
Abstract: The protein α-synuclein is the main component of Lewy bodies, the neuron-associated aggregates seen in Parkinson disease and other neurodegenerative pathologies. An 11-residue segment, which we term ...The protein α-synuclein is the main component of Lewy bodies, the neuron-associated aggregates seen in Parkinson disease and other neurodegenerative pathologies. An 11-residue segment, which we term NACore, appears to be responsible for amyloid formation and cytotoxicity of human α-synuclein. Here we describe crystals of NACore that have dimensions smaller than the wavelength of visible light and thus are invisible by optical microscopy. As the crystals are thousands of times too small for structure determination by synchrotron X-ray diffraction, we use micro-electron diffraction to determine the structure at atomic resolution. The 1.4 Å resolution structure demonstrates that this method can determine previously unknown protein structures and here yields, to our knowledge, the highest resolution achieved by any cryo-electron microscopy method to date. The structure exhibits protofibrils built of pairs of face-to-face β-sheets. X-ray fibre diffraction patterns show the similarity of NACore to toxic fibrils of full-length α-synuclein. The NACore structure, together with that of a second segment, inspires a model for most of the ordered portion of the toxic, full-length α-synuclein fibril, presenting opportunities for the design of inhibitors of α-synuclein fibrils.
History
DepositionMay 5, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 9, 2015Provider: repository / Type: Initial release
Revision 1.1Sep 23, 2015Group: Database references
Revision 1.2Oct 7, 2015Group: Database references
Revision 1.3Nov 30, 2016Group: Experimental preparation
Revision 1.4Sep 6, 2017Group: Author supporting evidence / Data collection / Category: em_image_scans / pdbx_audit_support
Item: _pdbx_audit_support.funding_organization / _pdbx_audit_support.grant_number
Revision 1.5Dec 18, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.6Mar 6, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

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Assembly

Deposited unit
A: Alpha-synuclein


Theoretical massNumber of molelcules
Total (without water)9401
Polymers9401
Non-polymers00
Water724
1
A: Alpha-synuclein

A: Alpha-synuclein

A: Alpha-synuclein

A: Alpha-synuclein

A: Alpha-synuclein

A: Alpha-synuclein

A: Alpha-synuclein

A: Alpha-synuclein

A: Alpha-synuclein

A: Alpha-synuclein


Theoretical massNumber of molelcules
Total (without water)9,40110
Polymers9,40110
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_585x,y+3,z1
crystal symmetry operation1_595x,y+4,z1
crystal symmetry operation2_556-x,y+1/2,-z+11
crystal symmetry operation2_566-x,y+3/2,-z+11
crystal symmetry operation2_576-x,y+5/2,-z+11
crystal symmetry operation2_586-x,y+7/2,-z+11
crystal symmetry operation2_596-x,y+9/2,-z+11
Unit cell
Length a, b, c (Å)17.930, 4.710, 33.030
Angle α, β, γ (deg.)90.000, 94.330, 90.000
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein/peptide Alpha-synuclein / Non-A beta component of AD amyloid / Non-A4 component of amyloid precursor / NACP


Mass: 940.074 Da / Num. of mol.: 1 / Mutation: A53T / Source method: obtained synthetically
Details: Synthetic peptide GVVHGVTTVA corresponding to segment 47-56 of human alpha-synuclein
Source: (synth.) Homo sapiens (human) / References: UniProt: P37840
#2: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 4 / Source method: isolated from a natural source / Formula: H2O

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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: Human alpha-synuclein / Type: COMPLEX / Entity ID: #1 / Source: MULTIPLE SOURCES
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES / Details: crystal
Crystal growTemperature: 310 K / Method: batch mode / pH: 7
Details: 1 mg of synthetic peptide GVVHGVTTVA was dissolved in 200 microliters of 50 mM phosphate buffer pH 7.0 and 0.1% w/v DMSO and shaken overnight in an orbital mixing plate
PH range: 7

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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
DiffractionMean temperature: 100 K
Diffraction sourceSource: ELECTRON MICROSCOPE / Type: OTHER / Wavelength: 0.0251 Å
DetectorDetector: CMOS / Date: Apr 20, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: electron
Radiation wavelengthWavelength: 0.0251 Å / Relative weight: 1
ReflectionResolution: 1.41→16.5 Å / Num. obs: 1120 / % possible obs: 86.9 % / Observed criterion σ(I): -3 / Redundancy: 3.7 % / Biso Wilson estimate: 22.483 Å2 / Rmerge F obs: 0.967 / Rmerge(I) obs: 0.236 / Rrim(I) all: 0.264 / Χ2: 0.831 / Net I/σ(I): 4.62 / Num. measured all: 4110
Reflection shell

Diffraction-ID: 1 / Rejects: _

Resolution (Å)Rmerge F obsRmerge(I) obsMean I/σ(I) obsNum. measured obsNum. possibleNum. unique obsRrim(I) all% possible all
1.41-1.480.6280.781.083231711000.89558.5
1.48-1.560.6640.5032.175231751400.57280
1.56-1.650.8240.4172.374171371250.4891.2
1.65-1.770.8260.4172.333751211160.49695.9
1.77-1.910.9370.293.784431241160.33493.5
1.91-2.090.9750.2625.195301331260.29894.7
2.09-2.340.9410.2696.275521291220.30394.6
2.34-2.70.9690.2036.3326385780.23791.8
2.7-3.310.9910.1448.0226388810.1792
3.31-4.680.9490.25611.7733785800.27994.1
4.68-16.50.9870.0787.188441360.187.8

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Phasing

PhasingMethod: molecular replacement
Phasing MRModel details: Phaser MODE: MR_AUTO

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Processing

Software
NameVersionClassification
XSCALEdata scaling
PHASER2.5.6phasing
REFMACrefinement
PDB_EXTRACT3.15data extraction
XDSdata reduction
Cootmodel building
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: Ideal model

Resolution: 1.41→16.47 Å / Cor.coef. Fo:Fc: 0.953 / Cor.coef. Fo:Fc free: 0.958 / WRfactor Rfree: 0.2879 / WRfactor Rwork: 0.2427 / FOM work R set: 0.6203 / SU B: 3.491 / SU ML: 0.111 / SU R Cruickshank DPI: 0.1115 / SU Rfree: 0.1137 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.112 / ESU R Free: 0.114 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2817 112 10 %RANDOM
Rwork0.2347 ---
obs0.2396 1006 86.73 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 50.34 Å2 / Biso mean: 18.371 Å2 / Biso min: 11.23 Å2
Baniso -1Baniso -2Baniso -3
1-1.08 Å20 Å20.01 Å2
2---1.13 Å2-0 Å2
3---0.05 Å2
Refinement stepCycle: final / Resolution: 1.41→16.47 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms66 0 0 4 70
Biso mean---24.58 -
Num. residues----10
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
ELECTRON CRYSTALLOGRAPHYr_bond_refined_d0.020.01966
ELECTRON CRYSTALLOGRAPHYr_bond_other_d0.1540.0269
ELECTRON CRYSTALLOGRAPHYr_angle_refined_deg1.9771.90591
ELECTRON CRYSTALLOGRAPHYr_angle_other_deg3.4423155
ELECTRON CRYSTALLOGRAPHYr_dihedral_angle_1_deg5.50659
ELECTRON CRYSTALLOGRAPHYr_dihedral_angle_2_deg75.764201
ELECTRON CRYSTALLOGRAPHYr_dihedral_angle_3_deg6.335157
ELECTRON CRYSTALLOGRAPHYr_chiral_restr0.0650.214
ELECTRON CRYSTALLOGRAPHYr_gen_planes_refined0.0060.0273
ELECTRON CRYSTALLOGRAPHYr_gen_planes_other0.0010.0213
ELECTRON CRYSTALLOGRAPHYr_mcbond_it3.9341.54239
ELECTRON CRYSTALLOGRAPHYr_mcbond_other1.9251.46838
ELECTRON CRYSTALLOGRAPHYr_mcangle_it5.2962.27942
LS refinement shellResolution: 1.409→1.574 Å / Total num. of bins used: 5
RfactorNum. reflection% reflection
Rfree0.329 26 -
Rwork0.336 239 -
all-265 -
obs--70.67 %

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