7ERH

Crystal structure of WT-TTR in complex with bithionol

7ERH の概要

• エントリーDOI: 10.2210/pdb7erh/pdb
• 分子名称: Transthyretin, 2,2'-sulfanediylbis(4,6-dichlorophenol), CALCIUM ION, ... (4 entities in total)
• 機能のキーワード: amyloidosis, inhibitor, complex, transport protein
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 35057.24

構造登録者

Yokoyama, T.,Kashihara, M.,Mizuguchi, M. (登録日: 2021-05-06, 公開日: 2021-11-24, 最終更新日: 2023-11-29)

主引用文献

Yokoyama, T.,Kashihara, M.,Mizuguchi, M.
Repositioning of the Anthelmintic Drugs Bithionol and Triclabendazole as Transthyretin Amyloidogenesis Inhibitors.
J.Med.Chem., 64:14344-14357, 2021

PubMed Abstract: Transthyretin (TTR) is a causative protein of TTR amyloidosis (ATTR amyloidosis), a general term for diseases characterized by deposition of TTR amyloid fibrils in specific organs. ATTR amyloidosis can be ameliorated by stabilization of the TTR tetramer through the binding of small molecules. Here, we show that the clinical anthelmintic drugs bithionol () and triclabendazole () potently inhibit aggregation of the amyloidogenic variant V30M-TTR. A competitive binding assay using a fluorescence probe showed that the binding affinity of with V30M-TTR was significantly higher than that of the first-in-class drug tafamidis (), and the binding affinity of was similar to that of . The crystallographic and thermodynamic analysis revealed that efficiently occupied the halogen-binding grooves of TTR, resulting in the favorable binding entropy. Multifaceted studies of anthelmintic drugs have the potential to reposition these drugs as ATTR amyloidosis inhibitors.

PubMed: 34547896
DOI: 10.1021/acs.jmedchem.1c00823

実験手法

X-RAY DIFFRACTION (1.55 Å)