+Open data
-Basic information
Entry | Database: PDB / ID: 8zlp | ||||||
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Title | apo WT polymorph 5a alpha-synuclein fibril | ||||||
Components | Alpha-synuclein | ||||||
Keywords | PROTEIN FIBRIL / amyloid fibril / complex | ||||||
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 | ||||||
Biological species | Homo sapiens (human) | ||||||
Method | ELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 3.5 Å | ||||||
Authors | Liu, K.E. / Tao, Y.Q. / Li, D. / Liu, C. | ||||||
Funding support | 1items
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Citation | Journal: 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 |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 8zlp.cif.gz | 95.5 KB | Display | PDBx/mmCIF format |
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PDB format | pdb8zlp.ent.gz | 75.9 KB | Display | PDB format |
PDBx/mmJSON format | 8zlp.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 8zlp_validation.pdf.gz | 1.2 MB | Display | wwPDB validaton report |
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Full document | 8zlp_full_validation.pdf.gz | 1.3 MB | Display | |
Data in XML | 8zlp_validation.xml.gz | 32.9 KB | Display | |
Data in CIF | 8zlp_validation.cif.gz | 47.9 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/zl/8zlp ftp://data.pdbj.org/pub/pdb/validation_reports/zl/8zlp | HTTPS FTP |
-Related structure data
Related structure data | 60232MC 8x7lC 8x7mC 8x7oC 8x7pC 8x7qC 8x7rC 8zliC 8zloC 8zmyC M: map data used to model this data C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
#1: Protein | Mass: 9804.276 Da / Num. of mol.: 6 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: SNCA, NACP, PARK1 / Production host: Escherichia coli (E. coli) / References: UniProt: P37840 Has ligand of interest | Y | Has protein modification | Y | |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: HELICAL ARRAY / 3D reconstruction method: helical reconstruction |
-Sample preparation
Component | Name: apo WT polymorph 5a alpha-synuclein fibril / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT |
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Source (natural) | Organism: Homo sapiens (human) |
Source (recombinant) | Organism: Escherichia coli (E. coli) |
Buffer solution | pH: 7.5 |
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Vitrification | Cryogen name: ETHANE |
-Electron microscopy imaging
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM |
Electron lens | Mode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 1000 nm |
Image recording | Electron dose: 55 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) |
-Processing
CTF correction | Type: NONE |
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Helical symmerty | Angular rotation/subunit: -0.861471 ° / Axial rise/subunit: 4.79997 Å / Axial symmetry: C1 |
3D reconstruction | Resolution: 3.5 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 34199 / Symmetry type: HELICAL |