Binding adaptability of chemical ligands to polymorphic α- synuclein amyloid fibrils

• 成果类型: Article
• 署名作者: Liu, Kaien; Tao, Youqi; Zhao, Qinyue; Xia, Wencheng; Li, Xiang; Zhang, Shenqing; Yao, Yuxuan; Xiang, Huaijiang; Han, Chao; Tan, Li; Sun, Bo; Li, Dan; Li, Ang; Liu, Cong
• 署名单位: Chinese Academy of Sciences; Shanghai Institute of Organic Chemistry, CAS; Shanghai Jiao Tong University; Shanghai Jiao Tong University; ShanghaiTech University; Chinese Academy of Sciences; Shanghai Institute of Organic Chemistry, CAS
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-11131
• DOI: 10.1073/pnas.2321633121
• 发表日期: 2024-08-27
• 关键词: alzheimers-disease; beta; tau

摘要

alpha- synuclein (alpha- 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 tures of these molecules when bound to the fibrils formed by E46K mutant alpha- syn and compared them to those bound with wild- type alpha- 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.