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Crystal structure of leukotriene A4 hydrolase in complex with kelatorphan, implications for design of zinc metallopeptidase inhibitors |
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| Authors: | Fredrik Tholander Bernard-Pierre Roques Marjolein M.G.M. Thunnissen |
| Affiliation: | a Department of Medical Biochemistry and Biophysics, Division of Chemistry II, Karolinska Institute, S-171 77 Stockholm, Sweden b Department of Molecular Biophysics, Kemicentrum, Lund University, S-221 00 Lund, Sweden c Départment de Pharmacochimie Moléculaire et Structurale, 4 Avenue de l’Observatoire, 75270 Paris Cedex 06, France d Pharmaleads, 11 rue Watt, 7513 Paris, France |
| Abstract: | 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. |
| Keywords: | Leukotriene Leukotriene B4 LTA4 hydrolase Aminopeptidase Cardiovascular Inflammation |
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