3CFN

Crystal structure of human transthyretin in complex with 1-anilino-8-naphthalene sulfonate

3CFN の概要

• エントリーDOI: 10.2210/pdb3cfn/pdb
• 関連するPDBエントリー: 3CFM 3CFQ 3CFT
• 分子名称: Transthyretin, 8-ANILINO-1-NAPHTHALENE SULFONATE (3 entities in total)
• 機能のキーワード: human transthyretin, amyloid, familial amyloid polyneurophaty, 1, 8-2an, disease mutation, glycoprotein, hormone, polyneuropathy, retinol-binding, secreted, thyroid hormone, transport, vitamin a, 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: 26521.71

構造登録者

Lima, L.-M.T.R.,Foguel, D.,Polikarpov, I. (登録日: 2008-03-04, 公開日: 2009-03-03, 最終更新日: 2023-08-30)

主引用文献

Lima, L.M.,Silva, V.D.,Palmieri, L.D.,Oliveira, M.C.,Foguel, D.,Polikarpov, I.
Identification of a novel ligand binding motif in the transthyretin channel.
Bioorg.Med.Chem., 18:100-110, 2010

PubMed Abstract: The design of therapeutic compounds targeting transthyretin (TTR) is challenging due to the low specificity of interaction in the hormone binding site. Such feature is highlighted by the interactions of TTR with diclofenac, a compound with high affinity for TTR, in two dissimilar modes, as evidenced by crystal structure of the complex. We report here structural analysis of the interactions of TTR with two small molecules, 1-amino-5-naphthalene sulfonate (1,5-AmNS) and 1-anilino-8-naphthalene sulfonate (1,8-ANS). Crystal structure of TTR:1,8-ANS complex reveals a peculiar interaction, through the stacking of the naphthalene ring between the side-chain of Lys15 and Leu17. The sulfonate moiety provides additional interaction with Lys15' and a water-mediated hydrogen bond with Thr119'. The uniqueness of this mode of ligand recognition is corroborated by the crystal structure of TTR in complex with the weak analogue 1,5-AmNS, the binding of which is driven mainly by hydrophobic partition and one electrostatic interaction between the sulfonate group and the Lys15. The ligand binding motif unraveled by 1,8-ANS may open new possibilities to treat TTR amyloid diseases by the elucidation of novel candidates for a more specific pharmacophoric pattern.

PubMed: 19954984
DOI: 10.1016/j.bmc.2009.11.025

実験手法

X-RAY DIFFRACTION (1.87 Å)