7DT3

Crystal structure of human transthyretin in complex with 4-chloro-9,10-dioxo-9,10-dihydroanthracene-2-carboxylic acid

7DT3 の概要

• エントリーDOI: 10.2210/pdb7dt3/pdb
• 分子名称: Transthyretin, CALCIUM ION, 4-chloranyl-9,10-bis(oxidanylidene)anthracene-2-carboxylic acid, ... (4 entities in total)
• 機能のキーワード: inhibitor, complex, t4-binding, amyloidosis, 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: 35274.53

構造登録者

Kitakami, R.,Yokoyama, T.,Mizuguchi, M. (登録日: 2021-01-04, 公開日: 2021-10-13, 最終更新日: 2023-11-29)

主引用文献

Kitakami, R.,Inui, K.,Nakagawa, Y.,Sawai, Y.,Katayama, W.,Yokoyama, T.,Okada, T.,Kanamitsu, K.,Nakagawa, S.,Toyooka, N.,Mizuguchi, M.
Inhibitory activities of anthraquinone and xanthone derivatives against transthyretin amyloidogenesis.
Bioorg.Med.Chem., 44:116292-116292, 2021

PubMed Abstract: Transthyretin is a tetrameric protein which functions as a transporter of thyroxine and retinol-binding protein. Misfolding and amyloid aggregation of transthyretin are known to cause wild-type and hereditary transthyretin amyloidosis. Stabilization of the transthyretin tetramer by low molecular weight compounds is an efficacious strategy to inhibit the aggregation pathway in the amyloidosis. Here, we investigated the inhibitory activities of anthraquinone and xanthone derivatives against amyloid aggregation, and found that xanthone-2-carboxylic acid with one chlorine or methyl group has strong inhibitory activity comparable with that of diflunisal, which is one of the best known stabilizers of transthyretin. X-ray crystallographic structures of transthyretin in complex with the compounds revealed that the introduction of chlorine, which is buried in a hydrophobic region, is important for the strong inhibitory effect of the stabilizer against amyloidogenesis. An in vitro absorption, distribution, metabolism and elimination (ADME) study and in vivo pharmacokinetic study demonstrated that the compounds have drug-like features, suggesting that they have potential as therapeutic agents to stabilize transthyretin.

PubMed: 34225167
DOI: 10.1016/j.bmc.2021.116292

実験手法

X-RAY DIFFRACTION (1.198 Å)