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Yorodumi- PDB-4znn: MicroED structure of the segment, GVVHGVTTVA, from the A53T famil... -
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-Basic information
Entry | Database: PDB / ID: 4znn | |||||||||
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Title | MicroED structure of the segment, GVVHGVTTVA, from the A53T familial mutant of Parkinson's disease protein, alpha-synuclein residues 47-56 | |||||||||
Components | Alpha-synuclein | |||||||||
Keywords | LIPID 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 / mitochondrial membrane organization / negative regulation of chaperone-mediated autophagy / 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 / 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 / dopamine uptake involved in synaptic transmission / dynein complex binding / regulation of dopamine secretion / positive regulation of receptor recycling / 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 / positive regulation of endocytosis / kinesin binding / cysteine-type endopeptidase inhibitor activity involved in apoptotic process / response to magnesium ion / synaptic vesicle endocytosis / regulation of presynapse assembly / negative regulation of serotonin uptake / alpha-tubulin binding / phospholipid metabolic process / supramolecular fiber organization / axon terminus / mitochondrial ATP synthesis coupled electron transport / inclusion body / fatty acid metabolic process / cellular response to copper ion / cellular response to epinephrine stimulus / Hsp70 protein binding / response to interleukin-1 / adult locomotory behavior / negative regulation of cysteine-type endopeptidase activity involved in apoptotic process / positive regulation of release of sequestered calcium ion into cytosol / SNARE binding / excitatory postsynaptic potential / long-term synaptic potentiation / phosphoprotein binding / protein tetramerization / regulation of transmembrane transporter activity / synapse organization / microglial cell activation / negative regulation of protein kinase activity / regulation of long-term neuronal synaptic plasticity / protein destabilization / ferrous iron binding / tau protein binding / positive regulation of protein serine/threonine kinase activity / PKR-mediated signaling / receptor internalization / phospholipid binding / activation of cysteine-type endopeptidase activity involved in apoptotic process / synaptic vesicle membrane / positive regulation of inflammatory response / positive regulation of peptidyl-serine phosphorylation / actin cytoskeleton / actin binding / cellular response to oxidative stress / histone binding / cell cortex / growth cone / chemical synaptic transmission / neuron apoptotic process / negative regulation of neuron apoptotic process / transcription cis-regulatory region binding / postsynapse / amyloid fibril formation / response to lipopolysaccharide / molecular adaptor activity / oxidoreductase activity / lysosome / response to xenobiotic stimulus Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) | |||||||||
Method | ELECTRON CRYSTALLOGRAPHY / electron crystallography / MOLECULAR REPLACEMENT / molecular replacement / cryo EM / Resolution: 1.41 Å | |||||||||
Authors | Rodriguez, 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
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Citation | Journal: 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 |
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-Structure visualization
Movie |
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Structure viewer | Molecule: MolmilJmol/JSmol |
-Downloads & links
-Download
PDBx/mmCIF format | 4znn.cif.gz | 11.9 KB | Display | PDBx/mmCIF format |
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PDB format | pdb4znn.ent.gz | 4.9 KB | Display | PDB format |
PDBx/mmJSON format | 4znn.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 4znn_validation.pdf.gz | 496.3 KB | Display | wwPDB validaton report |
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Full document | 4znn_full_validation.pdf.gz | 495.9 KB | Display | |
Data in XML | 4znn_validation.xml.gz | 5.8 KB | Display | |
Data in CIF | 4znn_validation.cif.gz | 7.2 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/zn/4znn ftp://data.pdbj.org/pub/pdb/validation_reports/zn/4znn | HTTPS FTP |
-Related structure data
Related structure data | 3001MC 3028C 4rikC 4rilC C: citing same article (ref.) M: map data used to model this data |
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Similar structure data |
-Links
-Assembly
Deposited unit |
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1 |
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Unit cell |
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-Components
#1: Protein/peptide | 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 |
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#2: Water | ChemComp-HOH / |
-Experimental details
-Experiment
Experiment | Method: ELECTRON CRYSTALLOGRAPHY / Number of used crystals: 1 |
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EM experiment | Aggregation state: 3D ARRAY / 3D reconstruction method: electron crystallography |
-Sample preparation
Component | Name: Human alpha-synuclein / Type: COMPLEX / Entity ID: #1 / Source: MULTIPLE SOURCES |
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Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES / Details: crystal |
Crystal grow | Temperature: 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 |
-Data collection
Experimental equipment | Model: Tecnai F20 / Image courtesy: FEI Company | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Microscopy | Model: FEI TECNAI F20 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Electron lens | Mode: DIFFRACTION | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Specimen holder | Cryogen: NITROGEN | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Diffraction | Mean temperature: 100 K | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Diffraction source | Source: ELECTRON MICROSCOPE / Type: OTHER / Wavelength: 0.0251 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Detector | Detector: CMOS / Date: Apr 20, 2015 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Radiation | Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: electron | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Radiation wavelength | Wavelength: 0.0251 Å / Relative weight: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reflection | Resolution: 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: _
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-Phasing
Phasing | Method: molecular replacement |
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Phasing MR | Model details: Phaser MODE: MR_AUTO |
-Processing
Software |
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Refinement | Method 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
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Solvent computation | Ion probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Displacement parameters | Biso max: 50.34 Å2 / Biso mean: 18.371 Å2 / Biso min: 11.23 Å2
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Refinement step | Cycle: final / Resolution: 1.41→16.47 Å
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Refine LS restraints |
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LS refinement shell | Resolution: 1.409→1.574 Å / Total num. of bins used: 5
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