Journal Article

Structural mechanism for specific binding of chemical compounds to amyloid fibrils

Tao, Youqi, Zhang, Shenqing, Xiang, Huaijiang, Tang, Wenjun, Li, Dan, Li, Ying, Gu, Wei, Tan, Li, Zhao, Qinyue, Han, Chao, Liu, Cong, Xia, Wencheng

2023

Overview

Amyloid fibril is an important pharmaceutical target for diagnostic and therapeutic treatment of neurodegenerative diseases. However, rational design of chemical compounds that interact with amyloid fibrils is unachievable due to the lack of mechanistic understanding of the ligand–fibril interaction. Here we used cryoelectron microscopy to survey the amyloid fibril-binding mechanism of a series of compounds including classic dyes, (pre)clinical imaging tracers and newly identified binders from high-throughput screening. We obtained clear densities of several compounds in complex with an α-synuclein fibril. These structures unveil the basic mechanism of the ligand–fibril interaction, which exhibits remarkable difference from the canonical ligand–protein interaction. In addition, we discovered a druggable pocket that is also conserved in the ex vivo α-synuclein fibrils from multiple system atrophy. Collectively, these findings expand our knowledge of protein–ligand interaction in the amyloid fibril state, which will enable rational design of amyloid binders in a medicinally beneficial way. Tao et al. reported a series of cryo-EM structures of α-synuclein fibrils in complex with amyloid dyes and imaging tracers, and identified druggable pockets in the fibrils of multiple system atrophy.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/535 / 631/92/56 / Atrophy / Binders / Binding / Biochemical Engineering / Biochemistry / Bioorganic Chemistry / Cell Biology / Chemical compounds / Chemistry / Chemistry and Materials Science / Chemistry/Food Science / Dyes / Fibrils / High-throughput screening / Ligands / Medical imaging / Neurodegenerative diseases / Proteins / Synuclein / Tracers