5U4F

Wild-type Transthyretin in complex with 1,1'-(1E)-(1,2-Ethenediyl)bis[2-chloro-4-boronic acid]benzene

5U4F の概要

• エントリーDOI: 10.2210/pdb5u4f/pdb
• 関連するPDBエントリー: 5U48 5U49 5U4A 5U4B 5U4C 5U4D 5U4E 5U4G
• 分子名称: Transthyretin, [(E)-ethene-1,2-diylbis(3-chloro-4,1-phenylene)]diboronic acid (3 entities in total)
• 機能のキーワード: boronic acids, medicinal chemistry, stilbene, covalent ligand, transport protein
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 28490.66

構造登録者

Windsor, I.W.,Smith, T.P.,Raines, R.T.,Forest, K.T. (登録日: 2016-12-03, 公開日: 2017-09-27, 最終更新日: 2024-10-23)

主引用文献

Smith, T.P.,Windsor, I.W.,Forest, K.T.,Raines, R.T.
Stilbene Boronic Acids Form a Covalent Bond with Human Transthyretin and Inhibit Its Aggregation.
J. Med. Chem., 60:7820-7834, 2017

PubMed Abstract: Transthyretin (TTR) is a homotetrameric protein. Its dissociation into monomers leads to the formation of fibrils that underlie human amyloidogenic diseases. The binding of small molecules to the thyroxin-binding sites in TTR stabilizes the homotetramer and attenuates TTR amyloidosis. Herein, we report on boronic acid-substituted stilbenes that limit TTR amyloidosis in vitro. Assays of affinity for TTR and inhibition of its tendency to form fibrils were coupled with X-ray crystallographic analysis of nine TTR·ligand complexes. The ensuing structure-function data led to a symmetrical diboronic acid that forms a boronic ester reversibly with serine 117. This diboronic acid inhibits fibril formation by both wild-type TTR and a common disease-related variant, V30M TTR, as effectively as does tafamidis, a small-molecule drug used to treat TTR-related amyloidosis in the clinic. These findings establish a new modality for covalent inhibition of fibril formation and illuminate a path for future optimization.

PubMed: 28920684
DOI: 10.1021/acs.jmedchem.7b00952

実験手法

X-RAY DIFFRACTION (1.5 Å)