8II2

Crystal structure of V30M-TTR in complex with BBM

8II2 の概要

• エントリーDOI: 10.2210/pdb8ii2/pdb
• 分子名称: Transthyretin, [3,5-bis(bromanyl)-4-oxidanyl-phenyl]-(2-ethyl-1-benzofuran-3-yl)methanone, CALCIUM ION, ... (4 entities in total)
• 機能のキーワード: thyroxine, amyloidosis, inhibitor, 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: 35573.41

構造登録者

Yokoyama, T. (登録日: 2023-02-24, 公開日: 2023-06-28, 最終更新日: 2024-05-29)

主引用文献

Mizuguchi, M.,Yokoyama, T.,Okada, T.,Nakagawa, Y.,Fujii, K.,Nabeshima, Y.,Toyooka, N.
Benziodarone and 6-hydroxybenziodarone are potent and selective inhibitors of transthyretin amyloidogenesis.
Bioorg.Med.Chem., 90:117370-117370, 2023

PubMed Abstract: Transthyretin amyloidosis is a progressive systemic disorder that is caused by the amyloid deposition of transthyretin in various organs. Stabilization of the native transthyretin is an effective strategy for the treatment of transthyretin amyloidosis. In this study we demonstrate that the clinically used uricosuric agent benziodarone is highly effective to stabilize the tetrameric structure of transthyretin. An acid-induced aggregation assay showed that benziodarone had strong inhibitory activity similar to that of tafamidis, which is currently used as a therapeutic agent for transthyretin amyloidosis. Moreover, a possible metabolite, 6-hydroxybenziodarone, retained the strong amyloid inhibitory activity of benziodarone. An ex vivo competitive binding assay using a fluorogenic probe showed that benziodarone and 6-hydroxybenziodarone were highly potent for selective binding to transthyretin in human plasma. An X-ray crystal structure analysis revealed that the halogenated hydroxyphenyl ring was located at the entrance of the thyroxine binding channel of transthyretin and that the benzofuran ring was located in the inner channel. These studies suggest that benziodarone and 6-hydroxybenziodarone would potentially be effective against transthyretin amyloidosis.

PubMed: 37311373
DOI: 10.1016/j.bmc.2023.117370

実験手法

X-RAY DIFFRACTION (1.798 Å)