3HJ0

Transthyretin in complex with a covalent small molecule kinetic stabilizer

3HJ0 の概要

• エントリーDOI: 10.2210/pdb3hj0/pdb
• 関連するPDBエントリー: 3CN1 3CN2 3CN3 3CN4
• 分子名称: Transthyretin, 4-fluorophenyl 3-[(E)-2-(4-hydroxy-3,5-dimethylphenyl)ethenyl]benzoate (3 entities in total)
• 機能のキーワード: hormone, growth factor, amyloid, disease mutation, gamma-carboxyglutamic acid, glycoprotein, polyneuropathy, retinol-binding, secreted, thyroid hormone, transport, vitamin a
• 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: 2
• 化学式量合計: 28343.51

構造登録者

Connelly, S.,Wilson, I.A.,Kelly, J.W. (登録日: 2009-05-20, 公開日: 2009-12-22, 最終更新日: 2014-11-19)

主引用文献

Choi, S.,Connelly, S.,Reixach, N.,Wilson, I.A.,Kelly, J.W.
Chemoselective small molecules that covalently modify one lysine in a non-enzyme protein in plasma.
Nat.Chem.Biol., 6:133-139, 2010

PubMed Abstract: A small molecule that could bind selectively to and then react chemoselectively with a non-enzyme protein in a complex biological fluid, such as blood, could have numerous practical applications. Herein, we report a family of designed stilbenes that selectively and covalently modify the prominent plasma protein transthyretin in preference to more than 4,000 other human plasma proteins. They react chemoselectively with only one of eight lysine e-amino groups within transthyretin. The crystal structure confirms the expected binding orientation of the stilbene substructure and the anticipated conjugating amide bond. These covalent transthyretin kinetic stabilizers exhibit superior amyloid inhibition potency compared to their noncovalent counterparts, and they prevent cytotoxicity associated with amyloidogenesis. Though there are a few prodrugs that, upon metabolic activation, react with a cysteine residue inactivating a specific non-enzyme, we are unaware of designed small molecules that react with one lysine e-amine within a specific non-enzyme protein in a complex biological fluid.

PubMed: 20081815
DOI: 10.1038/nchembio.281

実験手法

X-RAY DIFFRACTION (1.34 Å)