5EN3

Crystal structure of human transthyretin in complex with luteolin-Cl at 1.25 A resolution

5EN3 の概要

• エントリーDOI: 10.2210/pdb5en3/pdb
• 関連するPDBエントリー: 4qxv
• 分子名称: Transthyretin, 2-[3,4-bis(oxidanyl)phenyl]-7-chloranyl-5-oxidanyl-chromen-4-one, SODIUM ION, ... (5 entities in total)
• 機能のキーワード: beta barrel, wild type human ttr, transthyretin, 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: 28279.17

構造登録者

Begum, A.,Nilsson, L.,Olofsson, A.,Sauer-Eriksson, A.E. (登録日: 2015-11-09, 公開日: 2016-04-20, 最終更新日: 2024-01-10)

主引用文献

Nilsson, L.,Larsson, A.,Begum, A.,Iakovleva, I.,Carlsson, M.,Brannstrom, K.,Sauer-Eriksson, A.E.,Olofsson, A.
Modifications of the 7-Hydroxyl Group of the Transthyretin Ligand Luteolin Provide Mechanistic Insights into Its Binding Properties and High Plasma Specificity.
Plos One, 11:e0153112-e0153112, 2016

PubMed Abstract: Amyloid formation of the plasma protein transthyretin (TTR) has been linked to familial amyloid polyneuropathy and senile systemic amyloidosis. Binding of ligands within its natural hormone binding site can stabilize the tetrameric structure and impair amyloid formation. We have recently shown that the flavonoid luteolin stabilizes TTR in human plasma with a very high selectivity. Luteolin, however, is inactivated in vivo via glucuronidation for which the preferred site is the hydroxy group at position 7 on its aromatic A-ring. We have evaluated the properties of two luteolin variants in which the 7-hydroxy group has been exchanged for a chlorine (7-Cl-Lut) or a methoxy group (7-MeO-Lut). Using an in vitro model, based on human liver microsomes, we verified that these modifications increase the persistence of the drug. Crystal structure determinations show that 7-Cl-Lut binds similarly to luteolin. The larger MeO substituent cannot be accommodated within the same space as the chlorine or hydroxy group and as a result 7-MeO-Lut binds in the opposite direction with the methoxy group in position 7 facing the solvent. Both 7-Cl-Lut and 7-MeO-Lut qualify as high-affinity binders, but in contrast to luteolin, they display a highly non-specific binding to other plasma components. The binding of the two conformations and the key-interactions to TTR are discussed in detail. Taken together, these results show a proof-of-concept that the persistence of luteolin towards enzymatic modification can be increased. We reveal two alternative high-affinity binding modes of luteolin to TTR and that modification in position 7 is restricted only to small substituents if the original orientation of luteolin should be preserved. In addition, the present work provides a general and convenient method to evaluate the efficacy of TTR-stabilizing drugs under conditions similar to an in vivo environment.

PubMed: 27050398
DOI: 10.1371/journal.pone.0153112

実験手法

X-RAY DIFFRACTION (1.25 Å)