4TM9

Crystal Structure of Human Transthyretin Thr119Trp Mutant

4TM9 の概要

• エントリーDOI: 10.2210/pdb4tm9/pdb
• 関連するPDBエントリー: 4TKW 4TL4 4TL5 4TLK 4TLS 4TLT 4TLU 4TNE 4TNF 4TNG
• 分子名称: Transthyretin (2 entities in total)
• 機能のキーワード: human transthyretin, amyloid, transthyretin, mutant, 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: 28009.35

構造登録者

Saelices, L.,Cascio, D.,Sawaya, M.,Eisenberg, D.S. (登録日: 2014-05-31, 公開日: 2015-10-21, 最終更新日: 2023-12-27)

主引用文献

Saelices, L.,Johnson, L.M.,Liang, W.Y.,Sawaya, M.R.,Cascio, D.,Ruchala, P.,Whitelegge, J.,Jiang, L.,Riek, R.,Eisenberg, D.S.
Uncovering the Mechanism of Aggregation of Human Transthyretin.
J.Biol.Chem., 290:28932-28943, 2015

PubMed Abstract: The tetrameric thyroxine transport protein transthyretin (TTR) forms amyloid fibrils upon dissociation and monomer unfolding. The aggregation of transthyretin has been reported as the cause of the life-threatening transthyretin amyloidosis. The standard treatment of familial cases of TTR amyloidosis has been liver transplantation. Although aggregation-preventing strategies involving ligands are known, understanding the mechanism of TTR aggregation can lead to additional inhibition approaches. Several models of TTR amyloid fibrils have been proposed, but the segments that drive aggregation of the protein have remained unknown. Here we identify β-strands F and H as necessary for TTR aggregation. Based on the crystal structures of these segments, we designed two non-natural peptide inhibitors that block aggregation. This work provides the first characterization of peptide inhibitors for TTR aggregation, establishing a novel therapeutic strategy.

PubMed: 26459562
DOI: 10.1074/jbc.M115.659912

実験手法

X-RAY DIFFRACTION (1.7 Å)