5E23

Human transthyretin (TTR) complexed with (2,7-Dibromo-fluoren-9-ylideneaminooxy)-acetic acid

5E23 の概要

• エントリーDOI: 10.2210/pdb5e23/pdb
• 関連するPDBエントリー: 4TQ8 4TQH 4TQI 4TQP
• 分子名称: Transthyretin, {[(2,7-dibromo-9H-fluoren-9-ylidene)amino]oxy}acetic acid, DIMETHYL SULFOXIDE, ... (4 entities in total)
• 機能のキーワード: human transthyretin (ttr), fibril formation inhibitors, fluorenyl based inhibitor, 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: 2
• 化学式量合計: 28043.90

構造登録者

Ciccone, L.,Nencetti, S.,Rossello, A.,Orlandini, E.,Stura, E.A. (登録日: 2015-09-30, 公開日: 2016-03-23, 最終更新日: 2024-01-10)

主引用文献

Ciccone, L.,Nencetti, S.,Rossello, A.,Stura, E.A.,Orlandini, E.
Synthesis and structural analysis of halogen substituted fibril formation inhibitors of Human Transthyretin (TTR).
J Enzyme Inhib Med Chem, 31:40-51, 2016

PubMed Abstract: Transthyretin (TTR), a β-sheet-rich tetrameric protein, in equilibrium with an unstable amyloidogenic monomeric form is responsible for extracellular deposition of amyloid fibrils, is associated with the onset of neurodegenerative diseases, such as senile systemic amyloidosis, familial amyloid polyneuropathy and familial amyloid cardiomyopathy. One of the therapeutic strategies is to use small molecules to stabilize the TTR tetramer and thus curb amyloid fibril formation. Here, we report the synthesis, the in vitro evaluation of several halogen substituted 9-fluorenyl- and di-benzophenon-based ligands and their three-dimensional crystallographic analysis in complex with TTR. The synthesized compounds bind TTR and stabilize the tetramer with different potency. Of these compounds, 2c is the best inhibitor. The dual binding mode prevalent in the absence of substitutions on the fluorenyl ring, is disfavored by (2,7-dichloro-fluoren-9-ylideneaminooxy)-acetic acid (1b), (2,7-dibromo-fluoren-9-ylideneaminooxy)-acetic acid (1c) and (E/Z)-((3,4-dichloro-phenyl)-methyleneaminooxy)-acetic acid (2c), all with halogen substitutions.

PubMed: 27067161
DOI: 10.3109/14756366.2016.1167048

実験手法

X-RAY DIFFRACTION (1.41 Å)