4N87

Crystal structure of V30M mutant human transthyretin complexed with glabridin

4N87 の概要

• エントリーDOI: 10.2210/pdb4n87/pdb
• 関連するPDBエントリー: 4N85 4N86
• 分子名称: Transthyretin, 4-[(3R)-8,8-dimethyl-3,4-dihydro-2H,8H-pyrano[2,3-f]chromen-3-yl]benzene-1,3-diol (3 entities in total)
• 機能のキーワード: transporter, thyroxine binding, 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: 35333.90

構造登録者

Yokoyama, T.,Kosaka, Y.,Mizuguchi, M. (登録日: 2013-10-17, 公開日: 2014-02-19, 最終更新日: 2024-03-20)

主引用文献

Yokoyama, T.,Kosaka, Y.,Mizuguchi, M.
Crystal structures of human transthyretin complexed with glabridin
J.Med.Chem., 57:1090-1096, 2014

PubMed Abstract: Transthyretin (TTR) is a plasma protein implicated in human amyloid diseases. Several small molecules that bind to the thyroxine-binding site of TTR have been shown to stabilize the TTR tetramer and to inhibit amyloid fibril formation of TTR. Herein, we demonstrated that glabridin (Glab), a prenylated isoflavan isolated from Glycyrrhiza glabra L., inhibited aggregation of TTR in a thioflavin assay. The TTR-Glab complex structure revealed a novel binding mode including a CH-π interaction with A108 and a hydrogen bond with K15. A structural comparison with the wild type-apo structure revealed that the CH-π interaction with A108 was strengthened by the induced-fit conformational change upon Glab binding. Furthermore, the binding of Glab induced a rotation of the T119 side chain, and the inclusion of a water molecule, leading to stabilization of the dimer-dimer interface. These results demonstrate that Glab is a novel inhibitor of TTR fibrillization and suggest the molecular mechanism by which Glab binding stabilizes the tetramer.

PubMed: 24422526
DOI: 10.1021/jm401832j

実験手法

X-RAY DIFFRACTION (1.794 Å)