4WNJ

Crystal structure of Transthyretin-quercetin complex

4WNJ の概要

• エントリーDOI: 10.2210/pdb4wnj/pdb
• 分子名称: Transthyretin, DIMETHYL SULFOXIDE, 3,5,7,3',4'-PENTAHYDROXYFLAVONE, ... (4 entities in total)
• 機能のキーワード: amyloidosis; protein misfolding, negative cooperativity, fibrillogenesis inhibitors, transthyretin stabilizers, 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: 28013.22

構造登録者

Zanotti, G.,Cianci, M.,Berni, R.,Folli, C. (登録日: 2014-10-13, 公開日: 2015-08-05, 最終更新日: 2024-01-10)

主引用文献

Cianci, M.,Folli, C.,Zonta, F.,Florio, P.,Berni, R.,Zanotti, G.
Structural evidence for asymmetric ligand binding to transthyretin.
Acta Crystallogr.,Sect.D, 71:1582-1592, 2015

PubMed Abstract: Human transthyretin (TTR) represents a notable example of an amyloidogenic protein, and several compounds that are able to stabilize its native state have been proposed as effective drugs in the therapy of TTR amyloidosis. The two thyroxine (T4) binding sites present in the TTR tetramer display negative binding cooperativity. Here, structures of TTR in complex with three natural polyphenols (pterostilbene, quercetin and apigenin) have been determined, in which this asymmetry manifests itself as the presence of a main binding site with clear ligand occupancy and related electron density and a second minor site with a much lower ligand occupancy. The results of an analysis of the structural differences between the two binding sites are consistent with such a binding asymmetry. The different ability of TTR ligands to saturate the two T4 binding sites of the tetrameric protein can be ascribed to the different affinity of ligands for the weaker binding site. In comparison, the high-affinity ligand tafamidis, co-crystallized under the same experimental conditions, was able to fully saturate the two T4 binding sites. This asymmetry is characterized by the presence of small but significant differences in the conformation of the cavity of the two binding sites. Molecular-dynamics simulations suggest the presence of even larger differences in solution. Competition binding assays carried out in solution revealed the presence of a preferential binding site in TTR for the polyphenols pterostilbene and quercetin that was different from the preferential binding site for T4. The TTR binding asymmetry could possibly be exploited for the therapy of TTR amyloidosis by using a cocktail of two drugs, each of which exhibits preferential binding for a distinct binding site, thus favouring saturation of the tetrameric protein and consequently its stabilization.

PubMed: 26249340
DOI: 10.1107/S1399004715010585

実験手法

X-RAY DIFFRACTION (1.398 Å)