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- PDB-9o4b: Cryo-EM structure of in-vitro alpha-synuclein fibril bound with E... -

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Basic information

Entry
Database: PDB / ID: 9o4b
TitleCryo-EM structure of in-vitro alpha-synuclein fibril bound with Exemplar-6 PET-radioligand
ComponentsAlpha-synuclein
KeywordsPROTEIN FIBRIL / alpha-synuclein / fibril / amyloid / STRUCTURAL PROTEIN
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 / positive regulation of neurotransmitter secretion / negative regulation of dopamine metabolic process / regulation of macrophage activation / positive regulation of inositol phosphate biosynthetic process / regulation of locomotion / negative regulation of microtubule polymerization / synaptic vesicle transport / 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 / synaptic vesicle endocytosis / kinesin binding / cysteine-type endopeptidase inhibitor activity / negative regulation of serotonin uptake / response to type II interferon / 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 / PKR-mediated signaling / synapse organization / regulation of long-term neuronal synaptic plasticity / 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)
MethodELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 2.59 Å
AuthorsSanchez, J.C. / Perez, R.M. / Borcik, C.G. / Guarino, D.S. / Dhavala, D.D. / Baumgardt, J.K. / Shaffer, K.D. / Kotzbauer, P.T. / Mach, R.H. / Rienstra, C.M. ...Sanchez, J.C. / Perez, R.M. / Borcik, C.G. / Guarino, D.S. / Dhavala, D.D. / Baumgardt, J.K. / Shaffer, K.D. / Kotzbauer, P.T. / Mach, R.H. / Rienstra, C.M. / Petersson, E.J. / Wright, E.R.
Funding support United States, 9items
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, J.C. / Perez, R.M. / Borcik, C.G. / Guarino, D.S. / Dhavala, D.D. / Baumgardt, J.K. / Shaffer, K.D. / Kotzbauer, P.T. / Mach, R.H. / Rienstra, C.M. / Petersson, E.J. / Wright, E.R.
History
DepositionApr 8, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 23, 2025Provider: repository / Type: Initial release
Revision 1.0Apr 23, 2025Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Apr 23, 2025Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Apr 23, 2025Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Apr 23, 2025Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Apr 23, 2025Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Apr 23, 2025Data content type: Mask / Part number: 1 / Data content type: Mask / Provider: repository / Type: Initial release
Revision 1.0Apr 23, 2025Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Alpha-synuclein
B: Alpha-synuclein
C: Alpha-synuclein
D: Alpha-synuclein
E: Alpha-synuclein
F: Alpha-synuclein
G: Alpha-synuclein
H: Alpha-synuclein
I: Alpha-synuclein
J: Alpha-synuclein
K: Alpha-synuclein
L: Alpha-synuclein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)177,79724
Polymers173,71312
Non-polymers4,08412
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable, cross-linking
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.: 12
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SNCA, NACP, PARK1
Production host: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
References: UniProt: P37840
#2: Chemical
ChemComp-A1B9H / 2-(3,4-dimethylphenoxy)-N-[3-(4-fluorophenyl)-1,2-oxazol-5-yl]acetamide


Mass: 340.348 Da / Num. of mol.: 12 / Source method: obtained synthetically / Formula: C19H17FN2O3 / 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: alpha-synuclein fibril with Exemplar-6 PET-radioligand
Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli BL21(DE3) (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: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 105000 X / Nominal defocus max: 2500 nm / Nominal defocus min: 500 nm / C2 aperture diameter: 70 µm
Specimen holderSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 40 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)
EM imaging opticsEnergyfilter name: GIF Bioquantum / Energyfilter slit width: 20 eV

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Processing

EM software
IDNameCategory
2EPUimage acquisition
7UCSF ChimeraXmodel fitting
8Cootmodel fitting
13RELION3D reconstruction
14PHENIXmodel refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Helical symmertyAngular rotation/subunit: -2.28 ° / Axial rise/subunit: 9.65 Å / Axial symmetry: C1
3D reconstructionResolution: 2.59 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 64493 / Symmetry type: HELICAL
Atomic model buildingPDB-ID: 9CK3

9ck3


Accession code: 9CK3 / Source name: PDB / Type: experimental model
RefinementHighest resolution: 2.59 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0015976
ELECTRON MICROSCOPYf_angle_d0.3368088
ELECTRON MICROSCOPYf_dihedral_angle_d9.657864
ELECTRON MICROSCOPYf_chiral_restr0.0521032
ELECTRON MICROSCOPYf_plane_restr0.001984

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