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- PDB-4rik: Amyloid forming segment, AVVTGVTAV, from the NAC domain of Parkin... -

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Basic information

Entry
Database: PDB / ID: 4rik
TitleAmyloid forming segment, AVVTGVTAV, from the NAC domain of Parkinson's disease protein alpha-synuclein, residues 69-77
ComponentsAlpha-synuclein
KeywordsLIPID BINDING PROTEIN / Amyloid / alpha-synuclein / Parkinson's Disease / Toxic Core / NAC
Function / homology
Function and homology information


regulation of phospholipase activity / negative regulation of monooxygenase activity / negative regulation of mitochondrial electron transport, NADH to ubiquinone / positive regulation of glutathione peroxidase activity / 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 ...regulation of phospholipase activity / negative regulation of monooxygenase activity / negative regulation of mitochondrial electron transport, NADH to ubiquinone / positive regulation of glutathione peroxidase activity / 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 / negative regulation of transporter activity / mitochondrial membrane organization / negative regulation of chaperone-mediated autophagy / regulation of reactive oxygen species biosynthetic process / regulation of synaptic vesicle recycling / 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 / regulation of norepinephrine uptake / SNARE complex assembly / positive regulation of neurotransmitter secretion / dopamine biosynthetic process / regulation of locomotion / positive regulation of inositol phosphate biosynthetic process / synaptic vesicle priming / regulation of macrophage activation / negative regulation of microtubule polymerization / synaptic vesicle transport / dynein complex binding / dopamine uptake involved in synaptic transmission / positive regulation of receptor recycling / regulation of dopamine secretion / protein kinase inhibitor activity / negative regulation of thrombin-activated receptor signaling pathway / response to type II interferon / cuprous ion binding / response to magnesium ion / positive regulation of exocytosis / synaptic vesicle exocytosis / positive regulation of endocytosis / kinesin binding / cysteine-type endopeptidase inhibitor activity involved in apoptotic process / mitochondrial ATP synthesis coupled electron transport / synaptic vesicle endocytosis / regulation of presynapse assembly / negative regulation of serotonin uptake / alpha-tubulin binding / phospholipid metabolic process / supramolecular fiber organization / axon terminus / inclusion body / cellular response to copper ion / cellular response to epinephrine stimulus / Hsp70 protein binding / response to interleukin-1 / : / adult locomotory behavior / positive regulation of release of sequestered calcium ion into cytosol / SNARE binding / excitatory postsynaptic potential / fatty acid metabolic process / long-term synaptic potentiation / phosphoprotein binding / protein tetramerization / regulation of transmembrane transporter activity / protein destabilization / negative regulation of protein kinase activity / microglial cell activation / synapse organization / regulation of long-term neuronal synaptic plasticity / ferrous iron binding / positive regulation of protein serine/threonine kinase activity / tau protein binding / PKR-mediated signaling / receptor internalization / : / phospholipid binding / synaptic vesicle membrane / positive regulation of inflammatory response / actin cytoskeleton / positive regulation of peptidyl-serine phosphorylation / actin binding / cell cortex / cellular response to oxidative stress / histone binding / growth cone / chemical synaptic transmission / neuron apoptotic process / negative regulation of neuron apoptotic process / postsynapse / response to lipopolysaccharide / amyloid fibril formation / molecular adaptor activity / lysosome / transcription cis-regulatory region binding / oxidoreductase activity / positive regulation of apoptotic process
Similarity search - Function
Synuclein / Alpha-synuclein / Synuclein
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.854 Å
AuthorsGuenther, E.L. / Sawaya, M.R. / Ivanova, M. / 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 1.4Feb 28, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.5Apr 3, 2024Group: Refinement description / Category: pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Alpha-synuclein


Theoretical massNumber of molelcules
Total (without water)8161
Polymers8161
Non-polymers00
Water543
1
A: Alpha-synuclein
x 10


Theoretical massNumber of molelcules
Total (without water)8,16010
Polymers8,16010
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)61.864, 4.799, 17.263
Angle α, β, γ (deg.)90.00, 104.13, 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 (for example, x,y+1,z, etc.). The other sheet is composed of the symmetry mate -x+1/2,y+1/2,-z+1, and its unit cell translations along b (for example, -x+1/2,y+3/2,-z+1, etc.).

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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: 815.953 Da / Num. of mol.: 1 / Source method: obtained synthetically
Details: Synthetic peptide AVVTGVTAV corresponding to segment 69-77 of human alpha-synuclein
Source: (synth.) Homo sapiens (human) / References: UniProt: P37840
#2: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 3 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 1.52 Å3/Da / Density % sol: 19.22 %
Crystal growTemperature: 273 K / Method: vapor diffusion, hanging drop / pH: 4.6
Details: 0.9M Ammonium Phosphate, 0.1M Sodium Acetate, pH 4.6, vapor diffusion, hanging drop, temperature 273K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-E / Wavelength: 0.9791 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Aug 23, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9791 Å / Relative weight: 1
ReflectionResolution: 1.85→100 Å / Num. all: 521 / Num. obs: 521 / % possible obs: 97.7 % / Observed criterion σ(I): -3 / Redundancy: 4.1 % / Rmerge(I) obs: 0.117 / Χ2: 0.961 / Net I/σ(I): 11.1
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2Diffraction-ID% possible all
1.85-1.9240.248431.02197.7
1.92-1.994.20.29531.073196.4
1.99-2.0840.261461.351100
2.08-2.194.60.209570.884198.3
2.19-2.334.20.179521.2931100
2.33-2.514.40.202530.933189.8
2.51-2.764.10.125400.7641100
2.76-3.1640.099540.8051100
3.16-3.994.40.083570.818196.6
3.99-1003.50.075660.7331100

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Phasing

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

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Processing

Software
NameVersionClassificationNB
SCALEPACKdata scaling
PHASER2.5.6phasing
REFMAC5refinement
PDB_EXTRACT3.15data extraction
DENZOdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: poly alanine

Resolution: 1.854→30 Å / Cor.coef. Fo:Fc: 0.978 / Cor.coef. Fo:Fc free: 0.961 / WRfactor Rfree: 0.236 / WRfactor Rwork: 0.19 / FOM work R set: 0.73 / SU B: 4.061 / SU ML: 0.112 / SU R Cruickshank DPI: 0.1735 / SU Rfree: 0.1526 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.173 / ESU R Free: 0.153 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2211 51 9.8 %RANDOM
Rwork0.1758 ---
all0.1802 470 --
obs0.1802 470 97.93 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 53.1 Å2 / Biso mean: 17.341 Å2 / Biso min: 6.25 Å2
Baniso -1Baniso -2Baniso -3
1--0.23 Å2-0 Å2-0.06 Å2
2---0.02 Å2-0 Å2
3---0.25 Å2
Refinement stepCycle: LAST / Resolution: 1.854→30 Å /
ProteinNucleic acidLigandSolventTotal
Num. atoms57 0 0 3 60
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0050.0256
X-RAY DIFFRACTIONr_bond_other_d0.0110.0263
X-RAY DIFFRACTIONr_angle_refined_deg1.1231.96578
X-RAY DIFFRACTIONr_angle_other_deg0.6023141
X-RAY DIFFRACTIONr_dihedral_angle_1_deg8.19858
X-RAY DIFFRACTIONr_dihedral_angle_3_deg5.082156
X-RAY DIFFRACTIONr_chiral_restr0.0490.214
X-RAY DIFFRACTIONr_gen_planes_refined0.0020.0260
X-RAY DIFFRACTIONr_gen_planes_other00.028
X-RAY DIFFRACTIONr_mcbond_it5.8521.47535
X-RAY DIFFRACTIONr_mcbond_other5.8511.36434
X-RAY DIFFRACTIONr_mcangle_it8.4062.04642
LS refinement shellResolution: 1.854→2.072 Å / Total num. of bins used: 5
RfactorNum. reflection% reflection
Rfree0.286 12 -
Rwork0.248 125 -
all-137 -
obs--98.56 %

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