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- EMDB-60226: BTA-2-bound E46K alpha-synuclein fibrils -

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Basic information

Entry
Database: EMDB / ID: EMD-60226
TitleBTA-2-bound E46K alpha-synuclein fibrils
Map data
Sample
  • Complex: BTA-2-bound E46K alpha-synuclein fibril
    • Protein or peptide: Alpha-synuclein
  • Ligand: ~{N},~{N}-dimethyl-4-(6-methyl-1,3-benzothiazol-2-yl)aniline
Keywordsamyloid fibril / complex / PROTEIN FIBRIL
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 synaptic vesicle recycling / regulation of reactive oxygen species biosynthetic process / 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 / mitochondrial ATP synthesis coupled electron transport / 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 / cuprous ion binding / positive regulation of endocytosis / synaptic vesicle exocytosis / positive regulation of exocytosis / kinesin binding / response to magnesium ion / cysteine-type endopeptidase inhibitor activity involved in apoptotic process / regulation of presynapse assembly / response to type II interferon / negative regulation of serotonin uptake / synaptic vesicle endocytosis / alpha-tubulin binding / supramolecular fiber organization / axon terminus / cellular response to copper ion / inclusion body / cellular response to epinephrine stimulus / phospholipid metabolic process / Hsp70 protein binding / response to interleukin-1 / : / SNARE binding / adult locomotory behavior / positive regulation of release of sequestered calcium ion into cytosol / excitatory postsynaptic potential / fatty acid metabolic process / positive regulation of protein serine/threonine kinase activity / phosphoprotein binding / protein tetramerization / long-term synaptic potentiation / negative regulation of protein kinase activity / microglial cell activation / regulation of long-term neuronal synaptic plasticity / regulation of transmembrane transporter activity / synapse organization / tau protein binding / ferrous iron binding / : / PKR-mediated signaling / protein destabilization / receptor internalization / phospholipid binding / positive regulation of peptidyl-serine phosphorylation / synaptic vesicle membrane / positive regulation of inflammatory response / actin cytoskeleton / actin binding / cellular response to oxidative stress / histone binding / growth cone / cell cortex / chemical synaptic transmission / neuron apoptotic process / molecular adaptor activity / negative regulation of neuron apoptotic process / amyloid fibril formation / response to lipopolysaccharide / oxidoreductase activity / lysosome / postsynapse / transcription cis-regulatory region binding / positive regulation of apoptotic process
Similarity search - Function
Synuclein / Alpha-synuclein / Synuclein
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
Methodhelical reconstruction / cryo EM / Resolution: 3.4 Å
AuthorsLiu KE / Tao YQ / Li D / Liu C
Funding support1 items
OrganizationGrant numberCountry
Not funded
CitationJournal: Proc Natl Acad Sci U S A / Year: 2024
Title: Binding adaptability of chemical ligands to polymorphic α-synuclein amyloid fibrils.
Authors: Kaien Liu / Youqi Tao / Qinyue Zhao / Wencheng Xia / Xiang Li / Shenqing Zhang / Yuxuan Yao / Huaijiang Xiang / Chao Han / Li Tan / Bo Sun / Dan Li / Ang Li / Cong Liu /
Abstract: α-synuclein (α-syn) assembles into structurally distinct fibril polymorphs seen in different synucleinopathies, such as Parkinson's disease and multiple system atrophy. Targeting these unique ...α-synuclein (α-syn) assembles into structurally distinct fibril polymorphs seen in different synucleinopathies, such as Parkinson's disease and multiple system atrophy. Targeting these unique fibril structures using chemical ligands holds diagnostic significance for different disease subtypes. However, the molecular mechanisms governing small molecules interacting with different fibril polymorphs remain unclear. Here, we investigated the interactions of small molecules belonging to four distinct scaffolds, with different α-syn fibril polymorphs. Using cryo-electron microscopy, we determined the structures of these molecules when bound to the fibrils formed by E46K mutant α-syn and compared them to those bound with wild-type α-syn fibrils. Notably, we observed that these ligands exhibit remarkable binding adaptability, as they engage distinct binding sites across different fibril polymorphs. While the molecular scaffold primarily steered the binding locations and geometries on specific sites, the conjugated functional groups further refined this adaptable binding by fine-tuning the geometries and binding sites. Overall, our finding elucidates the adaptability of small molecules binding to different fibril structures, which sheds light on the diagnostic tracer and drug developments tailored to specific pathological fibril polymorphs.
History
DepositionMay 20, 2024-
Header (metadata) releaseSep 11, 2024-
Map releaseSep 11, 2024-
UpdateSep 11, 2024-
Current statusSep 11, 2024Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_60226.png

Downloads & links

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Map

FileDownload / File: emd_60226.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 256 pix.
= 212.48 Å		0.83 Å/pix.
x 256 pix.
= 212.48 Å		0.83 Å/pix.
x 256 pix.
= 212.48 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.83 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.00941
Minimum - Maximum-0.03611773 - 0.06598857
Average (Standard dev.)0.0005706396 (±0.0034866752)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 212.48 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_60226_half_map_1.map
Projections & Slices
AxesZYX

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Half map: #2

Fileemd_60226_half_map_2.map
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Sample components

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Entire : BTA-2-bound E46K alpha-synuclein fibril

EntireName: BTA-2-bound E46K alpha-synuclein fibril
Components
  • Complex: BTA-2-bound E46K alpha-synuclein fibril
    • Protein or peptide: Alpha-synuclein
  • Ligand: ~{N},~{N}-dimethyl-4-(6-methyl-1,3-benzothiazol-2-yl)aniline

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Supramolecule #1: BTA-2-bound E46K alpha-synuclein fibril

SupramoleculeName: BTA-2-bound E46K alpha-synuclein fibril / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Alpha-synuclein

MacromoleculeName: Alpha-synuclein / type: protein_or_peptide / ID: 1 / Number of copies: 10 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 5.402157 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
KKGVVHGVAT VAEKTKEQVT NVGGAVVTGV TAVAQKTVEG AGSIAAATGF VKKDQ

UniProtKB: Alpha-synuclein

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Macromolecule #2: ~{N},~{N}-dimethyl-4-(6-methyl-1,3-benzothiazol-2-yl)aniline

MacromoleculeName: ~{N},~{N}-dimethyl-4-(6-methyl-1,3-benzothiazol-2-yl)aniline
type: ligand / ID: 2 / Number of copies: 10 / Formula: A1L13
Molecular weightTheoretical: 268.377 Da

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Experimental details

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Structure determination

Methodcryo EM
Processinghelical reconstruction
Aggregation statehelical array

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Sample preparation

BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 55.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 1.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Final reconstructionApplied symmetry - Helical parameters - Δz: 2.40514 Å
Applied symmetry - Helical parameters - Δ&Phi: -179.403 °
Applied symmetry - Helical parameters - Axial symmetry: C1 (asymmetric)
Resolution.type: BY AUTHOR / Resolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 16191
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

6l4s

Final angle assignmentType: NOT APPLICABLE
FSC plot (resolution estimation)

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