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- EMDB-70093: Cryo-EM structure of in-vitro alpha-synuclein fibril bound with E... -

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Basic information

Entry
Database: EMDB / ID: EMD-70093
TitleCryo-EM structure of in-vitro alpha-synuclein fibril bound with Exemplar-6 PET-radioligand
Map data
Sample
  • Complex: alpha-synuclein fibril with Exemplar-6 PET-radioligand
    • Protein or peptide: Alpha-synuclein
  • Ligand: 2-(3,4-dimethylphenoxy)-N-[3-(4-fluorophenyl)-1,2-oxazol-5-yl]acetamide
Keywordsalpha-synuclein / fibril / amyloid / STRUCTURAL PROTEIN / PROTEIN FIBRIL
Function / homology
Function and homology information


negative regulation of mitochondrial electron transport, NADH to ubiquinone / : / neutral lipid metabolic process / regulation of acyl-CoA biosynthetic process / negative regulation of dopamine uptake involved in synaptic transmission / negative regulation of norepinephrine uptake / response to desipramine / positive regulation of SNARE complex assembly / positive regulation of hydrogen peroxide catabolic process / supramolecular fiber ...negative regulation of mitochondrial electron transport, NADH to ubiquinone / : / neutral lipid metabolic process / regulation of acyl-CoA biosynthetic process / negative regulation of dopamine uptake involved in synaptic transmission / negative regulation of norepinephrine uptake / response to desipramine / positive regulation of SNARE complex assembly / positive regulation of hydrogen peroxide catabolic process / supramolecular fiber / regulation of synaptic vesicle recycling / negative regulation of chaperone-mediated autophagy / mitochondrial membrane organization / regulation of reactive oxygen species biosynthetic process / positive regulation of protein localization to cell periphery / negative regulation of platelet-derived growth factor receptor signaling pathway / negative regulation of exocytosis / regulation of glutamate secretion / dopamine biosynthetic process / response to iron(II) ion / negative regulation of thrombin-activated receptor signaling pathway / SNARE complex assembly / negative regulation of dopamine metabolic process / positive regulation of neurotransmitter secretion / regulation of macrophage activation / positive regulation of inositol phosphate biosynthetic process / regulation of locomotion / synaptic vesicle transport / negative regulation of microtubule polymerization / regulation of norepinephrine uptake / synaptic vesicle priming / transporter regulator activity / dopamine uptake involved in synaptic transmission / protein kinase inhibitor activity / regulation of dopamine secretion / mitochondrial ATP synthesis coupled electron transport / positive regulation of receptor recycling / dynein complex binding / cuprous ion binding / nuclear outer membrane / response to magnesium ion / positive regulation of exocytosis / synaptic vesicle exocytosis / positive regulation of endocytosis / kinesin binding / synaptic vesicle endocytosis / cysteine-type endopeptidase inhibitor activity / response to type II interferon / negative regulation of serotonin uptake / regulation of presynapse assembly / alpha-tubulin binding / beta-tubulin binding / phospholipase binding / behavioral response to cocaine / supramolecular fiber organization / cellular response to fibroblast growth factor stimulus / phospholipid metabolic process / inclusion body / cellular response to epinephrine stimulus / Hsp70 protein binding / enzyme inhibitor activity / axon terminus / response to interleukin-1 / regulation of microtubule cytoskeleton organization / cellular response to copper ion / positive regulation of release of sequestered calcium ion into cytosol / SNARE binding / adult locomotory behavior / excitatory postsynaptic potential / protein tetramerization / phosphoprotein binding / microglial cell activation / ferrous iron binding / fatty acid metabolic process / regulation of long-term neuronal synaptic plasticity / synapse organization / PKR-mediated signaling / phospholipid binding / receptor internalization / protein destabilization / tau protein binding / terminal bouton / positive regulation of inflammatory response / long-term synaptic potentiation / synaptic vesicle membrane / actin cytoskeleton / actin binding / growth cone / cellular response to oxidative stress / neuron apoptotic process / cell cortex / histone binding / response to lipopolysaccharide / microtubule binding / amyloid fibril formation / chemical synaptic transmission / negative regulation of neuron apoptotic process / molecular adaptor activity / mitochondrial outer membrane / oxidoreductase activity
Similarity search - Function
Synuclein / Alpha-synuclein / Synuclein
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
Methodhelical reconstruction / cryo EM / Resolution: 2.59 Å
AuthorsSanchez JC / Perez RM / Borcik CG / Guarino DS / Dhavala DD / Baumgardt JK / Shaffer KD / Kotzbauer PT / Mach RH / Rienstra CM ...Sanchez JC / Perez RM / Borcik CG / Guarino DS / Dhavala DD / Baumgardt JK / Shaffer KD / Kotzbauer PT / Mach RH / Rienstra CM / Petersson EJ / Wright ER
Funding support United States, 9 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)U24GM139168 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)T32GM135066 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)F32GM149118 United States
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)RF1NS110436 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)P41GM136463 United States
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)RF1 NS103873 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)T32-GM133398 United States
National Institutes of Health/National Institute on Aging (NIH/NIA)F31 AG090063 United States
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)U19-NS110456 United States
CitationJournal: To Be Published
Title: Complementary Structural and Chemical Biology Methods Reveal the Basis for Selective Radioligand Binding to Alpha-Synuclein in MSA Tissue
Authors: Sanchez JC / Perez RM / Borcik CG / Guarino DS / Dhavala DD / Baumgardt JK / Shaffer KD / Kotzbauer PT / Mach RH / Rienstra CM / Petersson EJ / Wright ER
History
DepositionApr 8, 2025-
Header (metadata) releaseApr 23, 2025-
Map releaseApr 23, 2025-
UpdateApr 23, 2025-
Current statusApr 23, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_70093.png

Downloads & links

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Map

FileDownload / File: emd_70093.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 360 pix.
= 300.24 Å		0.83 Å/pix.
x 360 pix.
= 300.24 Å		0.83 Å/pix.
x 360 pix.
= 300.24 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.834 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.003
Minimum - Maximum-0.013519915 - 0.034409504
Average (Standard dev.)0.00013534454 (±0.0012699629)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions360360360
Spacing360360360
CellA=B=C: 300.24 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_70093_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_70093_half_map_1.map
Projections & Slices
AxesZYX

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Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_70093_half_map_2.map
Projections & Slices
AxesZYX

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Slices (1/2)
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Histogram

Histogram (log scale)

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Sample components

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Entire : alpha-synuclein fibril with Exemplar-6 PET-radioligand

EntireName: alpha-synuclein fibril with Exemplar-6 PET-radioligand
Components
  • Complex: alpha-synuclein fibril with Exemplar-6 PET-radioligand
    • Protein or peptide: Alpha-synuclein
  • Ligand: 2-(3,4-dimethylphenoxy)-N-[3-(4-fluorophenyl)-1,2-oxazol-5-yl]acetamide

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Supramolecule #1: alpha-synuclein fibril with Exemplar-6 PET-radioligand

SupramoleculeName: alpha-synuclein fibril with Exemplar-6 PET-radioligand
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: 12 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 14.476108 KDa
Recombinant expressionOrganism: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
SequenceString:
MDVFMKGLSK AKEGVVAAAE KTKQGVAEAA GKTKEGVLYV GSKTKEGVVH GVATVAEKTK EQVTNVGGAV VTGVTAVAQK TVEGAGSIA AATGFVKKDQ LGKNEEGAPQ EGILEDMPVD PDNEAYEMPS EEGYQDYEPE A

UniProtKB: Alpha-synuclein

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Macromolecule #2: 2-(3,4-dimethylphenoxy)-N-[3-(4-fluorophenyl)-1,2-oxazol-5-yl]ace...

MacromoleculeName: 2-(3,4-dimethylphenoxy)-N-[3-(4-fluorophenyl)-1,2-oxazol-5-yl]acetamide
type: ligand / ID: 2 / Number of copies: 12 / Formula: A1B9H
Molecular weightTheoretical: 340.348 Da

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Experimental details

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Structure determination

Methodcryo EM
Processinghelical reconstruction
Aggregation statefilament

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Sample preparation

BufferpH: 7.4
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Specialist opticsEnergy filter - Name: GIF Bioquantum / Energy filter - Slit width: 20 eV
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 40.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 70.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.5 µm / Nominal defocus min: 0.5 µm / Nominal magnification: 105000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Final reconstructionApplied symmetry - Helical parameters - Δz: 9.65 Å
Applied symmetry - Helical parameters - Δ&Phi: -2.28 °
Applied symmetry - Helical parameters - Axial symmetry: C1 (asymmetric)
Resolution.type: BY AUTHOR / Resolution: 2.59 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION / Number images used: 64493
Startup modelType of model: OTHER
Details: relion_helix_inimodel2d used to generate initial model from 2D classes
Final angle assignmentType: NOT APPLICABLE
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

9ck3


Chain - Source name: PDB / Chain - Initial model type: experimental model
Output model

PDB-9o4b:
Cryo-EM structure of in-vitro alpha-synuclein fibril bound with Exemplar-6 PET-radioligand

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