4Y9C

Crystal structure of V30M mutated transthyretin with bromide in complex with alpha-mangostin

4Y9C の概要

• エントリーDOI: 10.2210/pdb4y9c/pdb
• 関連するPDBエントリー: 4PWE 4Y9B 4Y9E 4Y9F 4Y9G
• 分子名称: Transthyretin, 1,3,6-trihydroxy-7-methoxy-2,8-bis(3-methylbut-2-en-1-yl)-9H-xanthen-9-one, BROMIDE ION, ... (4 entities in total)
• 機能のキーワード: transthyretin, natural product, inhibitor, transporter, transport protein-inhibitor complex, transport protein/inhibitor
• 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: 35985.51

構造登録者

Yokoyama, T.,Mizuguchi, M. (登録日: 2015-02-17, 公開日: 2015-09-09, 最終更新日: 2023-11-08)

主引用文献

Yokoyama, T.,Ueda, M.,Ando, Y.,Mizuguchi, M.
Discovery of gamma-Mangostin as an Amyloidogenesis Inhibitor
Sci Rep, 5:13570-13570, 2015

PubMed Abstract: Transthyretin (TTR) is a homotetrameric protein involved in human hereditary amyloidoses. The discovery and development of small molecules that inhibit the amyloid fibril formation of TTR is one of the therapeutic strategies for these diseases. Herein, we discovered that γ-mangostin (γ-M) is an effective inhibitor against the amyloid fibril formation of V30M amyloidogenic TTR. In-vitro binding assays revealed that γ-M was the most potent of the selected xanthone derivatives, and it bound to the thyroxine (T4)-binding sites and stabilized the TTR tetramer. X-ray crystallographic analysis revealed the diagonal binding mode of γ-M and the two binding sites of chloride ions at the T4-binding site. One of the chloride ions was replaced with a water molecule in the α-mangostin complex, which is a methylated derivative of γ-M. The stronger inhibitory potency of γ-M could be explained by the additional hydrogen bonds with the chloride ion. The present study establishes γ-M as a novel inhibitor of TTR fibrillization.

PubMed: 26310724
DOI: 10.1038/srep13570

実験手法

X-RAY DIFFRACTION (1.49 Å)