3NEX

V30M mutant human transthyretin (TTR) complexed with GC-24 (V30M:GC-24)

3NEX の概要

• エントリーDOI: 10.2210/pdb3nex/pdb
• 関連するPDBエントリー: 3KGS 3KGT 3KGU 3NEE 3NEO 3NES
• 分子名称: Transthyretin, GLYCEROL, [4-(3-BENZYL-4-HYDROXYBENZYL)-3,5-DIMETHYLPHENOXY]ACETIC ACID, ... (4 entities in total)
• 機能のキーワード: transport protein, ttr, transthyretin, amyloid, gc-1, gc-24
• 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: 26407.64

構造登録者

Trivella, D.B.B.,Polikarpov, I. (登録日: 2010-06-09, 公開日: 2010-11-24, 最終更新日: 2024-02-21)

主引用文献

Trivella, D.B.,Sairre, M.I.,Foguel, D.,Lima, L.M.,Polikarpov, I.
The binding of synthetic triiodo l-thyronine analogs to human transthyretin: molecular basis of cooperative and non-cooperative ligand recognition.
J.Struct.Biol., 173:323-332, 2011

PubMed Abstract: Transthyretin (TTR) is a tetrameric β-sheet-rich transporter protein directly involved in human amyloid diseases. Several classes of small molecules can bind to TTR delaying its amyloid fibril formation, thus being promising drug candidates to treat TTR amyloidoses. In the present study, we characterized the interactions of the synthetic triiodo L-thyronine analogs and thyroid hormone nuclear receptor TRβ-selective agonists GC-1 and GC-24 with the wild type and V30M variant of human transthyretin (TTR). To achieve this aim, we conducted in vitro TTR acid-mediated aggregation and isothermal titration calorimetry experiments and determined the TTR:GC-1 and TTR:GC-24 crystal structures. Our data indicate that both GC-1 and GC-24 bind to TTR in a non-cooperative manner and are good inhibitors of TTR aggregation, with dissociation constants for both hormone binding sites (HBS) in the low micromolar range. Analysis of the crystal structures of TTRwt:GC-1(24) complexes and their comparison with the TTRwt X-ray structure bound to its natural ligand thyroxine (T4) suggests, at the molecular level, the basis for the cooperative process displayed by T4 and the non-cooperative process provoked by both GC-1 and GC-24 during binding to TTR.

PubMed: 20937391
DOI: 10.1016/j.jsb.2010.10.003

実験手法

X-RAY DIFFRACTION (1.7 Å)