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

Tholander, Fredrik; Rogues, Bernard-Pierre; Fournie-Zaluski, Marie-Claude; Thunnissen, Marjolein LU and Haeggstrom, Jesper Z. (2010) In FEBS Letters 584(15). p.3446-3451
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'... (More)
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. (Less)
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author
organization
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Contribution to journal
publication status
published
subject
keywords
Cardiovascular, Aminopeptidase, LTA(4) hydrolase, Leukotriene, Leukotriene B-4, Inflammation
in
FEBS Letters
volume
584
issue
15
pages
3446 - 3451
publisher
Wiley-Blackwell
external identifiers
  • wos:000281033600034
  • scopus:77955273560
ISSN
1873-3468
DOI
10.1016/j.febslet.2010.06.044
language
English
LU publication?
yes
id
7482288c-5158-4c80-84da-f96cf3f6eb12 (old id 1673770)
date added to LUP
2010-09-23 08:06:16
date last changed
2018-05-29 11:41:40
@article{7482288c-5158-4c80-84da-f96cf3f6eb12,
  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.},
  author       = {Tholander, Fredrik and Rogues, Bernard-Pierre and Fournie-Zaluski, Marie-Claude and Thunnissen, Marjolein and Haeggstrom, Jesper Z.},
  issn         = {1873-3468},
  keyword      = {Cardiovascular,Aminopeptidase,LTA(4) hydrolase,Leukotriene,Leukotriene B-4,Inflammation},
  language     = {eng},
  number       = {15},
  pages        = {3446--3451},
  publisher    = {Wiley-Blackwell},
  series       = {FEBS Letters},
  title        = {Crystal structure of leukotriene A(4) hydrolase in complex with kelatorphan, implications for design of zinc metallopeptidase inhibitors},
  url          = {http://dx.doi.org/10.1016/j.febslet.2010.06.044},
  volume       = {584},
  year         = {2010},
}