2VJ8

Complex of human leukotriene A4 hydrolase with a hydroxamic acid inhibitor

2VJ8 の概要

• エントリーDOI: 10.2210/pdb2vj8/pdb
• 分子名称: LTA4H PROTEIN, ZINC ION, YTTERBIUM (III) ION, ... (7 entities in total)
• 機能のキーワード: hydroxamic acid, leukotriene hydrolase, zinc, protease, hydrolase, metalloprotease
• 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: 70477.09

構造登録者

Thunnissen, M.M.G.M.,Andersson, B.,Wong, C.-H.,Samuelsson, B.,Haeggstrom, J.Z. (登録日: 2007-12-07, 公開日: 2008-01-15, 最終更新日: 2023-12-13)

主引用文献

Thunnissen, M.M.G.M.,Andersson, B.,Wong, C.-H.,Samuelsson, B.,Haeggstrom, J.Z.
Crystal Structures of Leukotriene A4 Hydrolase in Complex with Captopril and Two Competitive Tight-Binding Inhibitors
Faseb J., 16:1648-, 2002

PubMed Abstract: Leukotriene (LT) A4 hydrolase/aminopeptidase is a bifunctional zinc enzyme that catalyzes the final step in the biosynthesis of LTB4, a potent chemoattractant and immune modulating lipid mediator. Here, we report a high-resolution crystal structure of LTA4 hydrolase in complex with captopril, a classical inhibitor of the zinc peptidase angiotensin-converting enzyme. Captopril makes few interactions with the protein, but its free thiol group is bound to the zinc, apparently accounting for most of its inhibitory action on LTA4 hydrolase. In addition, we have determined the structures of LTA4 hydrolase in complex with two selective tight-binding inhibitors, a thioamine and a hydroxamic acid. Their common benzyloxyphenyl tail, designed to mimic the carbon backbone of LTA4, binds into a narrow hydrophobic cavity in the protein. The free hydroxyl group of the hydroxamic acid makes a suboptimal, monodentate complex with the zinc, and strategies for improved inhibitor design can be deduced from the structure. Taken together, the three crystal structures provide the molecular basis for the divergent pharmacological profiles of LTA4 hydrolase inhibitors. Moreover, they help define the binding pocket for the fatty acid-derived epoxide LTA4 as well as the subsites for a tripeptide substrate, which in turn have important implications for the molecular mechanisms of enzyme catalyses.

PubMed: 12207002
DOI: 10.1096/FJ.01-1017FJE

実験手法

X-RAY DIFFRACTION (1.8 Å)