ArticleProceedings of the National Academy of Sciences of the United States of America2024
Binding adaptability of chemical ligands to polymorphic α-synuclein amyloid fibrils.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed.
- Structures of dye-bound transthyretin amyloid fibrils from abdominal fat biopsies.Nature communications · 2026Article
- Machine learning-assisted screening of small-molecule drugs for suppressing protein aggregation and ROS generation based on ECL and CV dual-mode signals amplified by DNA.Chemical science · 2026Article
- Formation of Condition-Dependent Alpha-Synuclein Fibril Strain in Artificial Cerebrospinal Fluid.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Characteristics and mechanisms of cognitive impairment in Parkinson disease.Nature reviews. Neurology · 2026Review
- Interactions Between Nutraceuticals and α-Synuclein Conformational States: Molecular Mechanisms and Neuroprotective Implications in Parkinson's Disease.International journal of molecular sciences · 2026Review
- Heterogeneous Dynamics of the Fuzzy Coat of Full-Length Phospho-Mimetic Tau Fibrils.Journal of the American Chemical Society · 2026Article
- Atomic structure and in situ visualization of native PMEL lamellae in melanosomes.Nature communications · 2025Article
- Alpha-synuclein fibril structures cluster into distinct classes.Biophysical journal · 2025Review
- Molecular Insight into Amyloid Fibril-Templated Aggregation of Biomarkers.ACS chemical neuroscience · 2025Article
- Binding Sites of a PET Ligand in Tau Fibrils with the Alzheimer's Disease Fold fromBiochemistry · 2025Article
- The potential of nanoparticle-based contrast agents in the diagnosis of neurodegenerative pathologies.Nanomedicine (London, England) · 2025Article
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Authors and funding
14 authors.
Funding
No grant is acknowledged in the PubMed record.
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 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.
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