3ESN

Human transthyretin (TTR) complexed with N-(3,5-Dibromo-4-hydroxyphenyl)-2,6-dimethylbenzamide

3ESN の概要

• エントリーDOI: 10.2210/pdb3esn/pdb
• 関連するPDBエントリー: 3ESO 3ESP
• 分子名称: Transthyretin, N-(3,5-dibromo-4-hydroxyphenyl)-2,6-dimethylbenzamide (3 entities in total)
• 機能のキーワード: hormone, growth factor, amyloid, disease mutation, gamma-carboxyglutamic acid, glycoprotein, polymorphism, 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: 28352.87

構造登録者

Connelly, S.,Wilson, I.A. (登録日: 2008-10-06, 公開日: 2009-04-07, 最終更新日: 2023-12-27)

主引用文献

Johnson, S.M.,Connelly, S.,Wilson, I.A.,Kelly, J.W.
Toward optimization of the second aryl substructure common to transthyretin amyloidogenesis inhibitors using biochemical and structural studies.
J.Med.Chem., 52:1115-1125, 2009

PubMed Abstract: Transthyretin (TTR) amyloidogenesis inhibitors are typically composed of two aromatic rings and a linker. We have previously established optimal structures for one aromatic ring and the linker. Herein, we employ a suboptimal linker and an optimal aryl-X substructure to rank order the desirability of aryl-Z substructures--using a library of 56 N-(3,5-dibromo-4-hydroxyphenyl)benzamides. Coconsideration of amyloid inhibition potency and ex vivo plasma TTR binding selectivity data reveal that 2,6, 2,5, 2, 3,4,5, and 3,5 substituted aryls bearing small substituents generate the most potent and selective inhibitors, in descending order. These benzamides generally lack undesirable thyroid hormone receptor binding and COX-1 inhibition activity. Three high-resolution TTR.inhibitor crystal structures (1.31-1.35 A) provide insight into why these inhibitors are potent and selective, enabling future structure-based design of TTR kinetic stabilizers.

PubMed: 19191553
DOI: 10.1021/jm801347s

実験手法

X-RAY DIFFRACTION (1.35 Å)