3CN0

Human transthyretin (TTR) in complex with 3,5-Dimethyl-4-hydroxystilbene

3CN0 の概要

• エントリーDOI: 10.2210/pdb3cn0/pdb
• 関連するPDBエントリー: 2QGB 3CN1 3CN2 3CN3 3CN4
• 分子名称: Transthyretin, 2,6-dimethyl-4-[(E)-2-phenylethenyl]phenol (3 entities in total)
• 機能のキーワード: transthyretin, tetramer, amyloid, disease mutation, gamma-carboxyglutamic acid, glycoprotein, polymorphism, polyneuropathy, retinol-binding, secreted, thyroid hormone, transport, vitamin a, hormone, 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: 28003.32

構造登録者

Connelly, S.,Wilson, I.A. (登録日: 2008-03-24, 公開日: 2008-10-28, 最終更新日: 2024-02-21)

主引用文献

Johnson, S.M.,Connelly, S.,Wilson, I.A.,Kelly, J.W.
Toward optimization of the linker substructure common to transthyretin amyloidogenesis inhibitors using biochemical and structural studies.
J.Med.Chem., 51:6348-6358, 2008

PubMed Abstract: To develop potent and highly selective transthyretin (TTR) amyloidogenesis inhibitors, it is useful to systematically optimize the three substructural elements that compose a typical TTR kinetic stabilizer: the two aryl rings and the linker joining them. Herein, we evaluated 40 bisaryl molecules based on 10 unique linker substructures to determine how these linkages influence inhibitor potency and selectivity. These linkers connect one unsubstituted aromatic ring to either a 3,5-X 2 or a 3,5-X 2-4-OH phenyl substructure (X = Br or CH 3). Coconsideration of amyloid inhibition and ex vivo plasma TTR binding selectivity data reveal that direct connection of the two aryls or linkage through nonpolar E-olefin or -CH 2CH 2- substructures generates the most potent and selective TTR amyloidogenesis inhibitors exhibiting minimal undesirable binding to the thyroid hormone nuclear receptor or the COX-1 enzyme. Five high-resolution TTR.inhibitor crystal structures (1.4-1.8 A) provide insight into why such linkers afford inhibitors with greater potency and selectivity.

PubMed: 18811132
DOI: 10.1021/jm800435s

実験手法

X-RAY DIFFRACTION (1.52 Å)