4DET

Crystal Structure of the Wild Type TTR Binding Kaempferol (TTRwt:KAE)

4DET の概要

• エントリーDOI: 10.2210/pdb4det/pdb
• 関連するPDBエントリー: 4DER 4DES 4DEU 4DEW
• 分子名称: Transthyretin, 3,5,7-TRIHYDROXY-2-(4-HYDROXYPHENYL)-4H-CHROMEN-4-ONE (3 entities in total)
• 機能のキーワード: beta sandwich, amyloidosis, flavonoid, 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: 25978.91

構造登録者

Trivella, D.B.B.,Polikarpov, I. (登録日: 2012-01-22, 公開日: 2012-11-21, 最終更新日: 2024-02-28)

主引用文献

Trivella, D.B.,Dos Reis, C.V.,Lima, L.M.,Foguel, D.,Polikarpov, I.
Flavonoid interactions with human transthyretin: Combined structural and thermodynamic analysis.
J.Struct.Biol., 180:143-153, 2012

PubMed Abstract: Transthyretin (TTR) is a carrier protein involved in human amyloidosis. The development of small molecules that may act as TTR amyloid inhibitors is a promising strategy to treat these pathologies. Here we selected and characterized the interaction of flavonoids with the wild type and the V30M amyloidogenic mutant TTR. TTR acid aggregation was evaluated in vitro in the presence of the different flavonoids. The best TTR aggregation inhibitors were studied by Isothermal Titration Calorimetry (ITC) in order to reveal their thermodynamic signature of binding to TTRwt. Crystal structures of TTRwt in complex with the top binders were also obtained, enabling us to in depth inspect TTR interactions with these flavonoids. The results indicate that changing the number and position of hydroxyl groups attached to the flavonoid core strongly influence flavonoid recognition by TTR, either by changing ligand affinity or its mechanism of interaction with the two sites of TTR. We also compared the results obtained for TTRwt with the V30M mutant structure in the apo form, allowing us to pinpoint structural features that may facilitate or hamper ligand binding to the V30M mutant. Our data show that the TTRwt binding site is labile and, in particular, the central region of the cavity is sensible for the small differences in the ligands tested and can be influenced by the Met30 amyloidogenic mutation, therefore playing important roles in flavonoid binding affinity, mechanism and mutant protein ligand binding specificities.

PubMed: 22842046
DOI: 10.1016/j.jsb.2012.07.008

実験手法

X-RAY DIFFRACTION (2.05 Å)