5BPP

Structure of human Leukotriene A4 hydrolase in complex with inhibitor 4AZ

Summary for 5BPP

• Entry DOI: 10.2210/pdb5bpp/pdb
• Related: 5AEN
• Descriptor: Leukotriene A-4 hydrolase, ZINC ION, YTTERBIUM (III) ION, ... (6 entities in total)
• Functional Keywords: inhibitor, complex, inflammation, enzyme, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm: P09960
• Total number of polymer chains: 1
• Total formula weight: 72402.17

Authors

Huang, J.,Dong, N.N.,Xiao, Q.,Ou, P.Y.,Wu, D.,Lu, W.Q. (deposition date: 2015-05-28, release date: 2016-08-10, Last modification date: 2024-03-20)

Primary citation

Xiao, Q.,Dong, N.N.,Yao, X.,Wu, D.,Lu, Y.,Mao, F.,Zhu, J.,Li, J.,Huang, J.,Chen, A.,Huang, L.,Wang, X.,Yang, G.,He, G.,Xu, Y.,Lu, W.Q.
Bufexamac ameliorates LPS-induced acute lung injury in mice by targeting LTA4H
Sci Rep, 6:25298-25298, 2016

PubMed Abstract: Neutrophils play an important role in the occurrence and development of acute lung injury (ALI). Leukotriene B4 (LTB4), a hydrolysis product of epoxide leukotriene A4 (LTA4) catalyzed by LTA4 hydrolase (LTA4H), is one of the most potent chemoattractants for neutrophil. Bufexamac is a drug widely used as an anti-inflammatory agent on the skin, however, the mechanism of action is still not fully understood. In this study, we found bufexamac was capable of specifically inhibiting LTA4H enzymatic activity and revealed the mode of interaction of bufexamac and LTA4H using X-ray crystallography. Moreover, bufexamac significantly prevented the production of LTB4 in neutrophil and inhibited the fMLP-induced neutrophil migration through inhibition of LTA4H. Finally, bufexamac significantly attenuated lung inflammation as reflected by reduced LTB4 levels and weakened neutrophil infiltration in bronchoalveolar lavage fluid from a lipopolysaccharide-induced ALI mouse model. In summary, our study indicates that bufexamac acts as an inhibitor of LTB4 biosynthesis and may have potential clinical applications for the treatment of ALI.

PubMed: 27126280
DOI: 10.1038/srep25298

Experimental method

X-RAY DIFFRACTION (2.03 Å)