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 entodopep- tidases and aminopeptidases. The inhibitor binds along the sequence signature for M1 aminopepti- dases, 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 S10 sub sites as well as strategies for design of inhibitors.
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