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- PDB-8xwd: Croy-EM structure of alpha synuclein fibril with EGCG -

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Basic information

Entry
Database: PDB / ID: 8xwd
TitleCroy-EM structure of alpha synuclein fibril with EGCG
ComponentsAlpha-synuclein
KeywordsPROTEIN FIBRIL / amyloid
Function / homology
Function and homology information


negative regulation of mitochondrial electron transport, NADH to ubiquinone / response to desipramine / 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 chaperone-mediated autophagy / regulation of synaptic vesicle recycling / regulation of reactive oxygen species biosynthetic process ...negative regulation of mitochondrial electron transport, NADH to ubiquinone / response to desipramine / 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 chaperone-mediated autophagy / regulation of synaptic vesicle recycling / regulation of reactive oxygen species biosynthetic process / positive regulation of protein localization to cell periphery / negative regulation of exocytosis / dopamine biosynthetic process / dopamine uptake involved in synaptic transmission / negative regulation of dopamine metabolic process / response to iron(II) ion / negative regulation of platelet-derived growth factor receptor signaling pathway / SNARE complex assembly / negative regulation of microtubule polymerization / negative regulation of thrombin-activated receptor signaling pathway / synaptic vesicle priming / Lewy body / synaptic vesicle transport / regulation of norepinephrine uptake / synaptic vesicle exocytosis / transporter regulator activity / protein kinase inhibitor activity / positive regulation of inositol phosphate biosynthetic process / positive regulation of receptor recycling / cuprous ion binding / positive regulation of exocytosis / nuclear outer membrane / dynein complex binding / synaptic transmission, dopaminergic / regulation of dopamine secretion / positive regulation of endocytosis / response to magnesium ion / negative regulation of serotonin uptake / kinesin binding / cysteine-type endopeptidase inhibitor activity / regulation of presynapse assembly / synaptic vesicle endocytosis / alpha-tubulin binding / beta-tubulin binding / phospholipase binding / behavioral response to cocaine / cellular response to fibroblast growth factor stimulus / supramolecular fiber organization / response to type II interferon / cellular response to epinephrine stimulus / inclusion body / response to interleukin-1 / Hsp70 protein binding / axon terminus / cellular response to copper ion / positive regulation of release of sequestered calcium ion into cytosol / enzyme inhibitor activity / glutathione metabolic process / SNARE binding / protein tetramerization / regulation of microtubule cytoskeleton organization / phosphoprotein binding / receptor internalization / protein destabilization / microglial cell activation / tubulin binding / ferrous iron binding / protein sequestering activity / phospholipid binding / synapse organization / PKR-mediated signaling / tau protein binding / enzyme activator activity / positive regulation of inflammatory response / actin cytoskeleton / terminal bouton / synaptic vesicle membrane / negative regulation of neuron apoptotic process / histone binding / actin binding / response to lipopolysaccharide / growth cone / cellular response to oxidative stress / cell cortex / oxidoreductase activity / microtubule binding / amyloid fibril formation / mitochondrial outer membrane / lysosome / transcription cis-regulatory region binding / mitochondrial inner membrane / positive regulation of apoptotic process / ribosome / mitochondrial matrix / Amyloid fiber formation / copper ion binding / protein domain specific binding / axon / lipid binding / neuronal cell body
Similarity search - Function
Synuclein / Alpha-synuclein / Synuclein
Similarity search - Domain/homology
Chem-KDH / Alpha-synuclein
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 3.1 Å
AuthorsLi, X. / Liu, C.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Adv Sci (Weinh) / Year: 2025
Title: Single-Molecule Insight Into α-Synuclein Fibril Structure and Mechanics Modulated by Chemical Compounds.
Authors: Xiang Li / Lulu Bi / Shenqing Zhang / Qianhui Xu / Wencheng Xia / Youqi Tao / Shaojuan Wu / Yanan Li / Weidong Le / Wenyan Kang / Dan Li / Bo Sun / Cong Liu /
Abstract: α-Syn fibrils, a key pathological hallmark of Parkinson's disease, is closely associated with disease initiation and progression. Several small molecules are found to bind or dissolve α-syn ...α-Syn fibrils, a key pathological hallmark of Parkinson's disease, is closely associated with disease initiation and progression. Several small molecules are found to bind or dissolve α-syn fibrils, offering potential therapeutic applications. Here, an innovative optical tweezers-based, fluorescence-combined approach is developed to probe the mechanical characteristics of α-syn fibrils at the single-molecule level. When subjected to axial stretching, local deformation within α-syn fibrils appeared at forces above 50 pN. These structural alternations occurred stepwise and are irreversible, suggesting unfolding of individual α-syn molecules or subdomains. Additionally, α-syn fibrils exhibits high heterogeneity in lateral disruption, with rupture force ranging from 50 to 500 pN. The impact of different compounds on the structure and mechanical features of α-syn fibrils is further examined. Notably, epigallocatechin gallate (EGCG) generally attenuates the rupture force of fibrils by wedging into the N-terminal polar groove and induces fibril dissociation. Conversely, copper chlorophyllin A (CCA) attaches to four different sites wrapping around the fibril core, reinforcing the stability of the fibril against rupture forces. The work offers an effective method for characterizing single-fibril properties and bridges compound-induced structural alternations with mechanical response. These insights are valuable for understanding amyloid fibril mechanics and their regulation by small molecules.
History
DepositionJan 16, 2024Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Feb 26, 2025Provider: repository / Type: Initial release
Revision 1.0Feb 26, 2025Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Feb 26, 2025Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Feb 26, 2025Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
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Revision 1.0Feb 26, 2025Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Feb 26, 2025Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Apr 23, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID / _em_admin.last_update
Revision 1.2Apr 30, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
C: Alpha-synuclein
D: Alpha-synuclein
E: Alpha-synuclein
A: Alpha-synuclein
F: Alpha-synuclein
B: Alpha-synuclein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)89,60712
Polymers86,8576
Non-polymers2,7506
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

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


Mass: 14476.108 Da / Num. of mol.: 6
Source method: isolated from a genetically manipulated source
Details: EGCG / Source: (gene. exp.) Homo sapiens (human) / Gene: SNCA, NACP, PARK1 / Production host: Escherichia coli K-12 (bacteria) / References: UniProt: P37840
#2: Chemical
ChemComp-KDH / (2R,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-chromen-3-yl 3,4,5-trihydroxybenzoate / (-)-Epigallocatechin-3-gallate / EGCG


Mass: 458.372 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C22H18O11 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: FILAMENT / 3D reconstruction method: helical reconstruction

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Sample preparation

ComponentName: Croy-EM structure of alpha synuclein fibril with EGCG / Type: ORGANELLE OR CELLULAR COMPONENT / Entity ID: #1 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli K-12 (bacteria)
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2200 nm / Nominal defocus min: 1400 nm
Image recordingElectron dose: 55 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Helical symmertyAngular rotation/subunit: -0.746 ° / Axial rise/subunit: 4.82 Å / Axial symmetry: C1
3D reconstructionResolution: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 207014 / Symmetry type: HELICAL

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