5A6I

V122I Transthyretin structure in complex with Tolcalpone

5A6I の概要

• エントリーDOI: 10.2210/pdb5a6i/pdb
• 分子名称: TRANSTHYRETIN, Tolcapone (3 entities in total)
• 機能のキーワード: transport protein, transprot protein, transthyretin, amyloid
• 由来する生物種: HOMO SAPIENS (HUMAN)
• 細胞内の位置: Secreted: P02766
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 14195.82

構造登録者

Reverter, D.,Gallego, P.,Santana, R.,Ventura, S. (登録日: 2015-06-26, 公開日: 2016-02-24, 最終更新日: 2024-05-08)

主引用文献

Reverter, D.,Gallego, P.,Santana, R.,Ventura, S.
Repositioning Tolcapone as a Potent Inhibitor of Transthyretin Amyloidogenesis and its Associated Cellular Toxicity
Nat.Commun., 7:10787-, 2016

PubMed Abstract: Transthyretin (TTR) is a plasma homotetrameric protein implicated in fatal systemic amyloidoses. TTR tetramer dissociation precedes pathological TTR aggregation. Native state stabilizers are promising drugs to treat TTR amyloidoses. Here we repurpose tolcapone, an FDA-approved molecule for Parkinson's disease, as a potent TTR aggregation inhibitor. Tolcapone binds specifically to TTR in human plasma, stabilizes the native tetramer in vivo in mice and humans and inhibits TTR cytotoxicity. Crystal structures of tolcapone bound to wild-type TTR and to the V122I cardiomyopathy-associated variant show that it docks better into the TTR T4 pocket than tafamidis, so far the only drug on the market to treat TTR amyloidoses. These data indicate that tolcapone, already in clinical trials for familial amyloid polyneuropathy, is a strong candidate for therapeutic intervention in these diseases, including those affecting the central nervous system, for which no small-molecule therapy exists.

PubMed: 26902880
DOI: 10.1038/NCOMMS10787

実験手法

X-RAY DIFFRACTION (1.86 Å)