Crystal structure of leukotriene A4 hydrolase in complex with kelatorphan, implications for design of zinc metallopeptidase inhibitors.
FEBS Lett
; 584(15): 3446-51, 2010 Aug 04.
Article
em En
| MEDLINE
| ID: mdl-20609366
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Inibidores de Proteases
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Zinco
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Desenho de Fármacos
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Metaloproteases
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Dipeptídeos
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Epóxido Hidrolases
Idioma:
En
Revista:
FEBS Lett
Ano de publicação:
2010
Tipo de documento:
Article
País de afiliação:
Suécia