Crystal structure of leukotriene A(4) hydrolase in complex with kelatorphan, implications for design of zinc metallopeptidase inhibitors

Research output: Contribution to journalArticle

Abstract

Leukotriene A(4) 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. (C) 2010 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Details

Authors
  • Fredrik Tholander
  • Bernard-Pierre Rogues
  • Marie-Claude Fournie-Zaluski
  • Marjolein Thunnissen
  • Jesper Z. Haeggstrom
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Biological Sciences

Keywords

  • Cardiovascular, Aminopeptidase, LTA(4) hydrolase, Leukotriene, Leukotriene B-4, Inflammation
Original languageEnglish
Pages (from-to)3446-3451
JournalFEBS Letters
Volume584
Issue number15
Publication statusPublished - 2010
Publication categoryResearch
Peer-reviewedYes