Crystal structure of leukotriene A4 hydrolase in complex with kelatorphan, implications for design of zinc metallopeptidase inhibitors

• Published in: FEBS letters Vol. 584; no. 15; pp. 3446 - 3451
• Main Authors: Tholander, Fredrik, Roques, Bernard-Pierre, Fournié-Zaluski, Marie-Claude, Thunnissen, Marjolein M.G.M., Haeggström, Jesper Z.
• Format: Journal Article
• Language: English
• Published: England 04-08-2010
• Subjects: Amino Acid Sequence; Aminopeptidase; Cardiovascular; Conserved Sequence; Crystallography, X-Ray; Dipeptides - chemistry; Drug Design; Enzyme Assays; Epoxide Hydrolases - chemistry; Epoxide Hydrolases - isolation & purification; high performance liquid chromatography; HPLC; Inflammation; kelatorphan; Leukotriene; leukotriene A4; Leukotriene A4 hydrolase; Leukotriene B4; LTA4; LTA4 hydrolase; LTA4H; Medicin och hälsovetenskap; Metalloproteases - antagonists & inhibitors; Models, Molecular; Molecular Sequence Data; N-[3(R)-[(hydroxyamino)carbonyl]-2-benzyl-1-oxopropyl]-L-alanine; p-NA; p-NAn; para-nitroanilide; para-nitroaniline; Protease Inhibitors - chemistry; Protease Inhibitors - pharmacology; Protein Binding - drug effects; SDS–PAGE; Sequence Alignment; sodium dodecyl polyacrylamide gel electrophoresis; Zinc - metabolism
• ISSN: 0014-5793; 1873-3468; 1873-3468
• DOI: 10.1016/j.febslet.2010.06.044

Leukotriene A4 hydrolase (LTA4H) is a key enzyme in the inflammatory process of mammals. It is an epoxide hydrolase and an aminopeptidase of the M1 family of the MA clan of Zn‐metallopeptidases. We have solved the crystal structure of LTA4H in complex with N‐[3(R)‐[(hydroxyamino)carbonyl]‐2‐benzyl‐1‐oxopropyl]‐L‐alanine, a potent inhibitor of several Zn‐metalloenzymes, both endopeptidases and aminopeptidases. The inhibitor binds along the sequence signature for M1 aminopeptidases, GXMEN. It exhibits bidentate chelation of the catalytic zinc and binds to LTA4H's enzymatically essential carboxylate recognition site. The structure gives clues to the binding of this inhibitor to related enzymes and thereby identifies residues of their S1′ sub sites as well as strategies for design of inhibitors.