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

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Basic information

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 phospholipase activity / negative regulation of monooxygenase activity / regulation of acyl-CoA biosynthetic process / negative regulation of dopamine uptake involved in synaptic transmission / negative regulation of norepinephrine uptake / positive regulation of glutathione peroxidase activity / positive regulation of SNARE complex assembly / positive regulation of hydrogen peroxide catabolic process ...negative regulation of mitochondrial electron transport, NADH to ubiquinone / neutral lipid metabolic process / regulation of phospholipase activity / negative regulation of monooxygenase activity / regulation of acyl-CoA biosynthetic process / negative regulation of dopamine uptake involved in synaptic transmission / negative regulation of norepinephrine uptake / positive regulation of glutathione peroxidase activity / positive regulation of SNARE complex assembly / positive regulation of hydrogen peroxide catabolic process / supramolecular fiber / negative regulation of transporter activity / negative regulation of chaperone-mediated autophagy / mitochondrial membrane organization / regulation of reactive oxygen species biosynthetic process / positive regulation of protein localization to cell periphery / regulation of synaptic vesicle recycling / negative regulation of platelet-derived growth factor receptor signaling pathway / negative regulation of exocytosis / regulation of glutamate secretion / response to iron(II) ion / regulation of norepinephrine uptake / dopamine biosynthetic process / SNARE complex assembly / positive regulation of neurotransmitter secretion / synaptic vesicle priming / dopamine uptake involved in synaptic transmission / regulation of macrophage activation / regulation of locomotion / positive regulation of inositol phosphate biosynthetic process / mitochondrial ATP synthesis coupled electron transport / negative regulation of microtubule polymerization / synaptic vesicle transport / dynein complex binding / positive regulation of receptor recycling / regulation of dopamine secretion / positive regulation of endocytosis / protein kinase inhibitor activity / negative regulation of thrombin-activated receptor signaling pathway / response to type II interferon / cuprous ion binding / positive regulation of exocytosis / synaptic vesicle exocytosis / cysteine-type endopeptidase inhibitor activity involved in apoptotic process / response to magnesium ion / kinesin binding / alpha-tubulin binding / regulation of presynapse assembly / synaptic vesicle endocytosis / negative regulation of serotonin uptake / localization / phospholipid metabolic process / supramolecular fiber organization / axon terminus / inclusion body / cellular response to copper ion / Hsp70 protein binding / cellular response to epinephrine stimulus / excitatory postsynaptic potential / response to interleukin-1 / adult locomotory behavior / SNARE binding / positive regulation of release of sequestered calcium ion into cytosol / fatty acid metabolic process / long-term synaptic potentiation / regulation of transmembrane transporter activity / ferrous iron binding / synapse organization / phospholipid binding / protein tetramerization / phosphoprotein binding / microglial cell activation / regulation of long-term neuronal synaptic plasticity / negative regulation of protein kinase activity / tau protein binding / protein destabilization / PKR-mediated signaling / negative regulation of cysteine-type endopeptidase activity involved in apoptotic process / positive regulation of protein serine/threonine kinase activity / receptor internalization / synaptic vesicle membrane / positive regulation of inflammatory response / activation of cysteine-type endopeptidase activity involved in apoptotic process / actin cytoskeleton / positive regulation of peptidyl-serine phosphorylation / cellular response to oxidative stress / actin binding / cell cortex / histone binding / growth cone / chemical synaptic transmission / postsynapse / neuron apoptotic process / negative regulation of neuron apoptotic process / amyloid fibril formation / response to lipopolysaccharide / lysosome / oxidoreductase activity / molecular adaptor activity / transcription cis-regulatory region binding
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 / 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: 0

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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