Crystal structure of leukotriene A4 hydrolase in complex with kelatorphan, implications for design of zinc metallopeptidase inhibitors.
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.
Tholander
Fredrik
F
Department of Medical Biochemistry and Biophysics, Division of Chemistry II, Karolinska Institute, S-171 77 Stockholm, Sweden. fredrik.tholander@molbio.su.se
Roques
Bernard-Pierre
BP
Fournié-Zaluski
Marie-Claude
MC
Thunnissen
Marjolein M G M
MM
Haeggström
Jesper Z
JZ
D000595:Amino Acid Sequence; D017124:Conserved Sequence; D018360:Crystallography, X-Ray; D004151:Dipeptides / Q000737:chemistry*; D015195:Drug Design; D057075:Enzyme Assays; D004851:Epoxide Hydrolases / Q000737:chemistry* / Q000302:isolation & purification; D045726:Metalloproteases / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011480:Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D016415:Sequence Alignment; D015032:Zinc / Q000378:metabolism*
D004151:Dipeptides; D011480:Protease Inhibitors; C042591:kelatorphan; D004851:Epoxide Hydrolases; D045726:Metalloproteases; D015032:Zinc; C043134:leukotriene A4 hydrolase