1TZ8

The monoclinic crystal structure of transthyretin in complex with diethylstilbestrol

1TZ8 の概要

• エントリーDOI: 10.2210/pdb1tz8/pdb
• 関連するPDBエントリー: 1TT6
• 分子名称: Transthyretin, ACETATE ION, DIMETHYL SULFOXIDE, ... (7 entities in total)
• 機能のキーワード: amyloid, transthyretin, diethylstilbestrol, protein stabilization, transport protein
• 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: 4
• 化学式量合計: 56295.86

構造登録者

Morais-de-Sa, E.M.,Pereira, P.J.B.,Saraiva, M.J.,Damas, A.M. (登録日: 2004-07-09, 公開日: 2004-10-12, 最終更新日: 2023-08-23)

主引用文献

Morais-de-Sa, E.M.,Pereira, P.J.B.,Saraiva, M.J.,Damas, A.M.
The crystal structure of transthyretin in complex with diethylstilbestrol: a promising template for the design of amyloid inhibitors
J.Biol.Chem., 279:53483-53490, 2004

PubMed Abstract: Transthyretin (TTR) is a homotetrameric plasma protein that, in conditions not yet completely understood, may aggregate, forming the fibrillar material associated with TTR amyloidosis. A number of reported experiments indicate that dissociation of the TTR tetramer occurs prior to fibril formation, and therefore, studies aiming at the discovery of compounds that stabilize the protein quaternary structure, thereby acting as amyloid inhibitors, are being performed. The ability of diethylstilbestrol (DES) to act as a competitive inhibitor for the thyroid hormone binding to TTR indicated a possible stabilizing effect of DES upon binding. Here we report the crystallographic study of DES binding to TTR. The structural data reveal two different binding modes, both located in the thyroxine binding channel. In both cases, DES binds deeply in the channel and establishes interactions with the equivalent molecule present in the adjacent binding site. The most remarkable features of DES interaction with TTR are its hydrophobic interactions within the protein halogen binding pockets, where its ethyl groups are snugly fitted, and the hydrogen bonds established at the center of the tetramer with Ser-117. Experiments concerning amyloid formation in vitro suggest that DES is effectively an amyloid inhibitor in acid-mediated fibrillogenesis and may be used for the design of more powerful drugs. The present study gave us further insight in the molecular mechanism by which DES competes with thyroid hormone binding to TTR and highlights key interactions between DES and TTR that oppose amyloid formation.

PubMed: 15469931
DOI: 10.1074/jbc.M408053200

実験手法

X-RAY DIFFRACTION (1.85 Å)