7W9R

Crystal structure of V30M-TTR in complex with naringenin derivative-18

7W9R の概要

• エントリーDOI: 10.2210/pdb7w9r/pdb
• 分子名称: Transthyretin, (2~{R})-2-[3,5-bis(chloranyl)-4-oxidanyl-phenyl]-5,7-bis(oxidanyl)-2,3-dihydrochromen-4-one (3 entities in total)
• 機能のキーワード: amyloidosis, complex, inhibitor, thyroxine, 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: 35367.45

構造登録者

Katayama, W.,Shimane, A.,Nabeshima, Y.,Yokoyama, T.,Mizuguchi, M. (登録日: 2021-12-10, 公開日: 2022-12-14, 最終更新日: 2023-11-29)

主引用文献

Mizuguchi, M.,Nakagawa, Y.,Inui, K.,Katayama, W.,Sawai, Y.,Shimane, A.,Kitakami, R.,Okada, T.,Nabeshima, Y.,Yokoyama, T.,Kanamitsu, K.,Nakagawa, S.,Toyooka, N.
Chlorinated Naringenin Analogues as Potential Inhibitors of Transthyretin Amyloidogenesis.
J.Med.Chem., 65:16218-16233, 2022

PubMed Abstract: Misfolding and aggregation of transthyretin are implicated in the fatal systemic disease known as transthyretin amyloidosis. Here, we report the development of a naringenin derivative bearing two chlorine atoms that will be efficacious for preventing aggregation of transthyretin in the eye. The amyloid inhibitory activity of the naringenin derivative was as strong as that of tafamidis, which is the first therapeutic agent targeting transthyretin in the plasma. X-ray crystal structures of the compounds in complex with transthyretin demonstrated that the naringenin derivative with one chlorine bound to the thyroxine-binding site of transthyretin in the forward mode and that the derivative with two chlorines bound to it in the reverse mode. An ex vivo competitive binding assay showed that naringenin derivatives exhibited more potent binding than tafamidis in the plasma. Furthermore, an in vivo pharmacokinetic study demonstrated that the dichlorinated derivative was significantly delivered to the eye.

PubMed: 36472374
DOI: 10.1021/acs.jmedchem.2c00511

実験手法

X-RAY DIFFRACTION (1.997 Å)