8AVA

Leukotriene A4 hydrolase in complex with 4-(4-benzylphenyl)-oxazol-2-amine

8AVA の概要

• エントリーDOI: 10.2210/pdb8ava/pdb
• 関連するPDBエントリー: 4L2L
• 分子名称: Leukotriene A-4 hydrolase, ZINC ION, YTTERBIUM (III) ION, ... (8 entities in total)
• 機能のキーワード: leukotriene b4, inflammation, inhibitor, complex, immune system
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 71759.25

構造登録者

Teder, T.,Haeggstrom, J.Z. (登録日: 2022-08-26, 公開日: 2023-05-03, 最終更新日: 2024-02-07)

主引用文献

Teder, T.,Konig, S.,Singh, R.,Samuelsson, B.,Werz, O.,Garscha, U.,Haeggstrom, J.Z.
Modulation of the 5-Lipoxygenase Pathway by Chalcogen-Containing Inhibitors of Leukotriene A 4 Hydrolase.
Int J Mol Sci, 24:-, 2023

PubMed Abstract: The 5-lipoxygenase (5-LOX) pathway gives rise to bioactive inflammatory lipid mediators, such as leukotrienes (LTs). 5-LOX carries out the oxygenation of arachidonic acid to the 5-hydroperoxy derivative and then to the leukotriene A epoxide which is converted to a chemotactic leukotriene B (LTB) by leukotriene A hydrolase (LTAH). In addition, LTAH possesses aminopeptidase activity to cleave the N-terminal proline of a pro-inflammatory tripeptide, prolyl-glycyl-proline (PGP). Based on the structural characteristics of LTAH, it is possible to selectively inhibit the epoxide hydrolase activity while sparing the inactivating, peptidolytic, cleavage of PGP. In the current study, chalcogen-containing compounds, 4-(4-benzylphenyl) thiazol-2-amine (ARM1) and its selenazole (TTSe) and oxazole (TTO) derivatives were characterized regarding their inhibitory and binding properties. All three compounds selectively inhibit the epoxide hydrolase activity of LTAH at low micromolar concentrations, while sparing the aminopeptidase activity. These inhibitors also block the 5-LOX activity in leukocytes and have distinct inhibition constants with recombinant 5-LOX. Furthermore, high-resolution structures of LTAH with inhibitors were determined and potential binding sites to 5-LOX were proposed. In conclusion, we present chalcogen-containing inhibitors which differentially target essential steps in the biosynthetic route for LTB and can potentially be used as modulators of inflammatory response by the 5-LOX pathway.

PubMed: 37108702
DOI: 10.3390/ijms24087539

実験手法

X-RAY DIFFRACTION (1.354 Å)