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

doi:10.1073/pnas.2321633121

	Binding adaptability of chemical ligands to polymorphic α-synuclein amyloid fibrils
	Liu, Kaien 1; Tao, Youqi 2,3; Zhao, Qiuyue 2,3; Xia, Wencheng 1; Li, Xiang 2,3; Zhang, Shengqing 2,3; Yao, Yuxuan 2,3; Xiang, Huaijinag 1; Han, Chao 1; Tan, Li 1; Sun, Bo4 ; Li, Dan 2,3; Li, Ang 1; Liu, Cong 1,5
	2024-08-22
发表期刊	PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA (IF:9.4[JCR-2023],10.8[5-Year])
ISSN	0027-8424
EISSN	1091-6490
卷号	121 期号:35 页码:e2321633121
发表状态	已发表
DOI	10.1073/pnas.2321633121
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.
关键词	alpha- synuclein amyloid fibril polymorphism protein-ligand interaction chemical ligands
URL	查看原文
收录类别	SCI
语种	英语
资助项目	National Natural Science Foundation (NSF) of China["82188101","92353302","32170683"] ; Science and Technology Commission of Shanghai Municipality[22JC1410400] ; Shanghai Pilot Program for Basic Research-Chinese Academy of Science, Shanghai Branch[CYJ-SHFY- 2022-005] ; Chinese Academy of Sciences Project for Young Scientists in Basic Research[YSBR-095]
WOS研究方向	Science & Technology - Other Topics
WOS类目	Multidisciplinary Sciences
WOS记录号	WOS:001407404900001
出版者	NATL ACAD SCIENCES
引用统计	正在获取...
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/414266
专题	生命科学与技术学院_PI研究组_孙博组
共同第一作者	Tao, Youqi
通讯作者	Liu, Cong
作者单位	1.Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201210, China 2.Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200030, China 3.Zhangjiang Institute for Advanced Study, Shanghai Jiao Tong University, Shanghai 200240, China 4.School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China 5.State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
推荐引用方式 GB/T 7714	Liu, Kaien,Tao, Youqi,Zhao, Qiuyue,et al. Binding adaptability of chemical ligands to polymorphic α-synuclein amyloid fibrils[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,2024,121(35):e2321633121.
APA	Liu, Kaien.,Tao, Youqi.,Zhao, Qiuyue.,Xia, Wencheng.,Li, Xiang.,...&Liu, Cong.(2024).Binding adaptability of chemical ligands to polymorphic α-synuclein amyloid fibrils.PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,121(35),e2321633121.
MLA	Liu, Kaien,et al."Binding adaptability of chemical ligands to polymorphic α-synuclein amyloid fibrils".PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 121.35(2024):e2321633121.