3M1O

Human Transthyretin (TTR) complexed with 2-((3,5-dichloro-4-hydroxyphenyl)amino)benzoic acid

3M1O の概要

• エントリーDOI: 10.2210/pdb3m1o/pdb
• 関連するPDBエントリー: 3IPB 3IPE 3IPG
• 分子名称: Transthyretin, 2-[(3,5-dichloro-4-hydroxyphenyl)amino]benzoic acid (3 entities in total)
• 機能のキーワード: amyloid, inhibitor, amyloidosis, disease mutation, gamma-carboxyglutamic acid, glycoprotein, hormone, neuropathy, secreted, thyroid hormone, transport
• 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: 28150.96

構造登録者

Kolstoe, S.E.,Wood, S.P. (登録日: 2010-03-05, 公開日: 2010-11-17, 最終更新日: 2023-09-06)

主引用文献

Kolstoe, S.E.,Mangione, P.P.,Bellotti, V.,Taylor, G.W.,Tennent, G.A.,Deroo, S.,Morrison, A.J.,Cobb, A.J.,Coyne, A.,McCammon, M.G.,Warner, T.D.,Mitchell, J.,Gill, R.,Smith, M.D.,Ley, S.V.,Robinson, C.V.,Wood, S.P.,Pepys, M.B.
Trapping of palindromic ligands within native transthyretin prevents amyloid formation.
Proc.Natl.Acad.Sci.USA, 107:20483-20488, 2010

PubMed Abstract: Transthyretin (TTR) amyloidosis is a fatal disease for which new therapeutic approaches are urgently needed. We have designed two palindromic ligands, 2,2'-(4,4'-(heptane-1,7-diylbis(oxy))bis(3,5-dichloro-4,1-phenylene)) bis(azanediyl)dibenzoic acid (mds84) and 2,2'-(4,4'-(undecane-1,11-diylbis(oxy))bis(3,5-dichloro-4,1-phenylene)) bis(azanediyl)dibenzoic acid (4ajm15), that are rapidly bound by native wild-type TTR in whole serum and even more avidly by amyloidogenic TTR variants. One to one stoichiometry, demonstrable in solution and by MS, was confirmed by X-ray crystallographic analysis showing simultaneous occupation of both T4 binding sites in each tetrameric TTR molecule by the pair of ligand head groups. Ligand binding by native TTR was irreversible under physiological conditions, and it stabilized the tetrameric assembly and inhibited amyloidogenic aggregation more potently than other known ligands. These superstabilizers are orally bioavailable and exhibit low inhibitory activity against cyclooxygenase (COX). They offer a promising platform for development of drugs to treat and prevent TTR amyloidosis.

PubMed: 21059958
DOI: 10.1073/pnas.1008255107

実験手法

X-RAY DIFFRACTION (1.2 Å)