8IG1

Crystal structure of wild-type transthyretin in complex with rafoxanide

8IG1 の概要

• エントリーDOI: 10.2210/pdb8ig1/pdb
• 分子名称: Transthyretin, ~{N}-[3-chloranyl-4-(4-chloranylphenoxy)phenyl]-3,5-bis(iodanyl)-2-oxidanyl-benzamide, SODIUM ION, ... (4 entities in total)
• 機能のキーワード: t4 carrier, transporter, amyloidosis, transferase
• 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: 35919.04

構造登録者

Yokoyama, T. (登録日: 2023-02-20, 公開日: 2023-08-16, 最終更新日: 2023-11-15)

主引用文献

Yokoyama, T.,Mizuguchi, M.,Nabeshima, Y.,Nakagawa, Y.,Okada, T.,Toyooka, N.,Kusaka, K.
Rafoxanide, a salicylanilide anthelmintic, interacts with human plasma protein transthyretin.
Febs J., 290:5158-5170, 2023

PubMed Abstract: Transthyretin (TTR) is a carrier protein for thyroid hormone thyroxine (T ) in plasma, placental cytosol, and cerebrospinal fluid. While the potential toxicity of small molecules that compete with T for binding to TTR should be carefully studied, these small molecules can also serve as anti-ATTR amyloidosis drugs by stabilizing the TTR structure. Here, we demonstrated that rafoxanide, an EU-approved anthelmintic drug for domesticated animals, binds to the T -binding site of TTR. An intrinsic fluorescence quenching assay showed that rafoxanide also binds to the thyroid hormone-related proteins, including serum albumin and thyroid hormone receptor β. Rafoxanide strongly inhibited TTR amyloidogenesis in fibrillization assay, but the binding of rafoxanide to TTR was interfered with in human plasma, probably due to interactions with thyroid hormone-related proteins. Protein crystallography provided clues for the optimization of binding affinity and selectivity. Our findings emphasize the importance of considering rafoxanide as both a possible thyroid-disrupting chemical and a lead compound for the development of new ATTR amyloidosis inhibitors.

PubMed: 37522420
DOI: 10.1111/febs.16915

実験手法

X-RAY DIFFRACTION (1.451 Å)