Crystal structure of leukotriene A(4) hydrolase in complex with kelatorphan, implications for design of zinc metallopeptidase inhibitors
(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)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/1673770
- author
- Tholander, Fredrik ; Rogues, Bernard-Pierre ; Fournie-Zaluski, Marie-Claude ; Thunnissen, Marjolein LU and Haeggstrom, Jesper Z.
- organization
- publishing date
- 2010
- type
- 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
- pmid:20609366
- 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
- 2016-04-01 13:38:18
- date last changed
- 2022-01-27 20:15:10
@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}}, keywords = {{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}}, doi = {{10.1016/j.febslet.2010.06.044}}, volume = {{584}}, year = {{2010}}, }