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- PDB-4ril: Structure of the amyloid forming segment, GAVVTGVTAVA, from the N... -

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Basic information

Entry
Database: PDB / ID: 4ril
TitleStructure of the amyloid forming segment, GAVVTGVTAVA, from the NAC domain of Parkinson's disease protein alpha-synuclein, residues 68-78, determined by electron diffraction
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 / dopamine biosynthetic process / regulation of norepinephrine uptake / positive regulation of neurotransmitter secretion / SNARE complex assembly / synaptic vesicle priming / dopamine uptake involved in synaptic transmission / regulation of macrophage activation / regulation of locomotion / mitochondrial ATP synthesis coupled electron transport / positive regulation of inositol phosphate biosynthetic process / 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 / synaptic vesicle exocytosis / positive regulation of 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 / axon terminus / supramolecular fiber organization / inclusion body / cellular response to copper ion / cellular response to epinephrine stimulus / excitatory postsynaptic potential / response to interleukin-1 / adult locomotory behavior / SNARE binding / Hsp70 protein binding / positive regulation of release of sequestered calcium ion into cytosol / fatty acid metabolic process / long-term synaptic potentiation / regulation of transmembrane transporter activity / synapse organization / ferrous iron binding / protein tetramerization / phospholipid 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 / phosphoprotein binding / activation of cysteine-type endopeptidase activity involved in apoptotic process / actin cytoskeleton / cellular response to oxidative stress / positive regulation of peptidyl-serine phosphorylation / actin binding / cell cortex / growth cone / histone binding / chemical synaptic transmission / postsynapse / neuron apoptotic process / negative regulation of neuron apoptotic process / amyloid fibril formation / response to lipopolysaccharide / lysosome / molecular adaptor activity / oxidoreductase 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: 1.43 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.
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
DepositionOct 6, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 26, 2015Provider: repository / Type: Initial release
Revision 1.1Sep 9, 2015Group: Database references
Revision 1.2Sep 23, 2015Group: Database references
Revision 1.3Oct 7, 2015Group: Database references
Revision 1.4Apr 25, 2018Group: Author supporting evidence / Data collection / Data processing
Category: diffrn_source / em_3d_reconstruction ...diffrn_source / em_3d_reconstruction / em_image_scans / em_single_particle_entity
Item: _diffrn_source.source
Revision 1.5Jun 30, 2021Group: Data collection / Category: diffrn_detector / Item: _diffrn_detector.detector
Revision 1.6Sep 20, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

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Structure viewerMolecule:
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Assembly

Deposited unit
A: Alpha-synuclein


Theoretical massNumber of molelcules
Total (without water)9441
Polymers9441
Non-polymers00
Water362
1
A: Alpha-synuclein
x 10


Theoretical massNumber of molelcules
Total (without water)9,44110
Polymers9,44110
Non-polymers00
Water18010
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation1_535x,y-2,z1
crystal symmetry operation1_545x,y-1,z1
crystal symmetry operation1_565x,y+1,z1
crystal symmetry operation1_575x,y+2,z1
crystal symmetry operation4_535-x+1/2,y-3/2,-z1
crystal symmetry operation4_545-x+1/2,y-1/2,-z1
crystal symmetry operation4_555-x+1/2,y+1/2,-z1
crystal symmetry operation4_565-x+1/2,y+3/2,-z1
crystal symmetry operation4_575-x+1/2,y+5/2,-z1
Unit cell
Length a, b, c (Å)70.810, 4.820, 16.790
Angle α, β, γ (deg.)90.00, 105.68, 90.00
Int Tables number5
Space group name H-MC121
DetailsThe biological unit is a pair of beta-sheets. One sheet is composed of chain A and unit cell translations along the b dimension. The other sheet is composed of the symmetry mate -x+1/2,y+1/2,-z, and unit cell translations along b.

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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: 944.083 Da / Num. of mol.: 1 / Source method: obtained synthetically
Details: Synthetic peptide GAVVTGVTAVA corresponding to segment 68-78 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.: 2 / 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: 4
EM experimentAggregation state: 3D ARRAY / 3D reconstruction method: electron crystallography

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Sample preparation

ComponentName: amyloid forming segment GAVVTGVTAVA from the NAC domain of alpha-synuclein
Type: COMPLEX
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE
CrystalDensity Matthews: 1.46 Å3/Da / Density % sol: 15.81 %
Crystal growTemperature: 310 K / Method: batch crystallization / pH: 4
Details: 1 mg of synthetic peptide GAVVTGVTAVA was dissolved in 1 ml of sterile water and shaken overnight in an orbital mixing plate, pH 4.0, batch crystallization, temperature 310K

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Data collection

Experimental equipment
Model: Tecnai F20 / Image courtesy: FEI Company
MicroscopyModel: FEI TECNAI F20
Electron gunAccelerating voltage: 200 kV / Illumination mode: FLOOD BEAM
Electron lensMode: DIFFRACTION
Specimen holderSpecimen holder model: GATAN 626 SINGLE TILT LIQUID NITROGEN CRYO TRANSFER HOLDER
Image recordingAverage exposure time: 3.5 sec. / Electron dose: 0.35 e/Å2 / Film or detector model: TVIPS TEMCAM-F416 (4k x 4k)
DiffractionMean temperature: 100 K
Diffraction sourceSource: ELECTRON MICROSCOPE / Type: TECNAI F20 TEM / Wavelength: 0.0251 Å
DetectorType: TVIPS F416 CMOS CAMERA / Detector: CMOS / Date: Aug 28, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: electron
Radiation wavelengthWavelength: 0.0251 Å / Relative weight: 1
ReflectionResolution: 1.43→16.43 Å / Num. all: 1073 / Num. obs: 1073 / % possible obs: 89.9 % / Redundancy: 4.4 % / Biso Wilson estimate: 10.33 Å2 / Rmerge(I) obs: 0.175 / Net I/σ(I): 5.5
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique all% possible all
1.43-1.64.40.5652.5124528682.5
3.2-16.433.80.081347812694

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Phasing

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

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Processing

Software
NameVersionClassificationNB
Aimless0.3.11data scaling
PHASER2.5.6phasing
BUSTER-TNTBUSTER 2.10.0refinement
PDB_EXTRACT3.15data extraction
XDSdata reduction
XSCALEdata scaling
BUSTERrefinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4RIK
Resolution: 1.43→16.43 Å / Cor.coef. Fo:Fc: 0.9126 / Cor.coef. Fo:Fc free: 0.9002 / SU R Cruickshank DPI: 0.108 / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.275 127 11.84 %RANDOM
Rwork0.2483 ---
all0.2512 1073 --
obs0.2512 1073 87.88 %-
Displacement parametersBiso max: 74.5 Å2 / Biso mean: 12.75 Å2 / Biso min: 3 Å2
Baniso -1Baniso -2Baniso -3
1--3.9876 Å20 Å2-1.5509 Å2
2--3.4908 Å20 Å2
3---0.4968 Å2
Refine analyzeLuzzati coordinate error obs: 0.305 Å
Refinement stepCycle: LAST / Resolution: 1.43→16.43 Å /
ProteinNucleic acidLigandSolventTotal
Num. atoms66 0 0 2 68
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
ELECTRON CRYSTALLOGRAPHYt_dihedral_angle_d16SINUSOIDAL2
ELECTRON CRYSTALLOGRAPHYt_trig_c_planes1HARMONIC2
ELECTRON CRYSTALLOGRAPHYt_gen_planes10HARMONIC5
ELECTRON CRYSTALLOGRAPHYt_it65HARMONIC20
ELECTRON CRYSTALLOGRAPHYt_nbd
ELECTRON CRYSTALLOGRAPHYt_improper_torsion
ELECTRON CRYSTALLOGRAPHYt_pseud_angle
ELECTRON CRYSTALLOGRAPHYt_chiral_improper_torsion11SEMIHARMONIC5
ELECTRON CRYSTALLOGRAPHYt_sum_occupancies
ELECTRON CRYSTALLOGRAPHYt_utility_distance
ELECTRON CRYSTALLOGRAPHYt_utility_angle
ELECTRON CRYSTALLOGRAPHYt_utility_torsion
ELECTRON CRYSTALLOGRAPHYt_ideal_dist_contact76SEMIHARMONIC4
ELECTRON CRYSTALLOGRAPHYt_bond_d65HARMONIC20.01
ELECTRON CRYSTALLOGRAPHYt_angle_deg90HARMONIC21.65
ELECTRON CRYSTALLOGRAPHYt_omega_torsion4.08
ELECTRON CRYSTALLOGRAPHYt_other_torsion6.49
LS refinement shellResolution: 1.43→1.6 Å / Total num. of bins used: 5
RfactorNum. reflection% reflection
Rfree0.331 41 14.34 %
Rwork0.2532 245 -
all0.2642 286 -
obs--87.88 %

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