5AKS

Transthyretin binding heterogeneity and anti-amyloidogenic activity of natural polyphenols and their metabolites: resveratrol-3-O- glucuronide

5AKS の概要

• エントリーDOI: 10.2210/pdb5aks/pdb
• 関連するPDBエントリー: 5AKT 5AKV 5AL0 5AL8
• 分子名称: TRANSTHYRETIN, SULFATE ION, Resveratrol-3-O-glucuronide, ... (5 entities in total)
• 機能のキーワード: transport protein, amyloid, fibrillogenesis, fibrillogenesis inhibitors, polyphenols, polyphenol metabolites, transthyretin, negative cooperativity
• 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: 28633.71

構造登録者

Florio, P.,Foll, C.,Cianci, M.,Del Rio, D.,Zanotti, G.,Berni, R. (登録日: 2015-03-05, 公開日: 2015-10-21, 最終更新日: 2024-01-10)

主引用文献

Florio, P.,Folli, C.,Cianci, M.,Del Rio, D.,Zanotti, G.,Berni, R.
Transthyretin Binding Heterogeneity and Anti-Amyloidogenic Activity of Natural Polyphenols and Their Metabolites
J.Biol.Chem., 290:29769-, 2015

PubMed Abstract: Transthyretin (TTR) is an amyloidogenic protein, the amyloidogenic potential of which is enhanced by a number of specific point mutations. The ability to inhibit TTR fibrillogenesis is known for several classes of compounds, including natural polyphenols, which protect the native state of TTR by specifically interacting with its thyroxine binding sites. Comparative analyses of the interaction and of the ability to protect the TTR native state for polyphenols, both stilbenoids and flavonoids, and some of their main metabolites have been carried out. A main finding of this investigation was the highly preferential binding of resveratrol and thyroxine, both characterized by negative binding cooperativity, to distinct sites in TTR, consistent with the data of x-ray analysis of TTR in complex with both ligands. Although revealing the ability of the two thyroxine binding sites of TTR to discriminate between different ligands, this feature has allowed us to evaluate the interactions of polyphenols with both resveratrol and thyroxine preferential binding sites, by using resveratrol and radiolabeled T4 as probes. Among flavonoids, genistein and apigenin were able to effectively displace resveratrol from its preferential binding site, whereas genistein also showed the ability to interact, albeit weakly, with the preferential thyroxine binding site. Several glucuronidated polyphenol metabolites did not exhibit significant competition for resveratrol and thyroxine preferential binding sites and lacked the ability to stabilize TTR. However, resveratrol-3-O-sulfate was able to significantly protect the protein native state. A rationale for the in vitro properties found for polyphenol metabolites was provided by x-ray analysis of their complexes with TTR.

PubMed: 26468275
DOI: 10.1074/JBC.M115.690172

実験手法

X-RAY DIFFRACTION (1.25 Å)