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| - | [[Image:2vj8.jpg|left|200px]] | + | {{Seed}} |
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| | {{STRUCTURE_2vj8| PDB=2vj8 | SCENE= }} | | {{STRUCTURE_2vj8| PDB=2vj8 | SCENE= }} |
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| - | '''COMPLEX OF HUMAN LEUKOTRIENE A4 HYDROLASE WITH A HYDROXAMIC ACID INHIBITOR'''
| + | ===COMPLEX OF HUMAN LEUKOTRIENE A4 HYDROLASE WITH A HYDROXAMIC ACID INHIBITOR=== |
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| - | ==Overview==
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| - | Leukotriene (LT) A4 hydrolase/aminopeptidase is a bifunctional zinc enzyme that catalyzes the final step in the biosynthesis of LTB4, a potent chemoattractant and immune modulating lipid mediator. Here, we report a high-resolution crystal structure of LTA4 hydrolase in complex with captopril, a classical inhibitor of the zinc peptidase angiotensin-converting enzyme. Captopril makes few interactions with the protein, but its free thiol group is bound to the zinc, apparently accounting for most of its inhibitory action on LTA4 hydrolase. In addition, we have determined the structures of LTA4 hydrolase in complex with two selective tight-binding inhibitors, a thioamine and a hydroxamic acid. Their common benzyloxyphenyl tail, designed to mimic the carbon backbone of LTA4, binds into a narrow hydrophobic cavity in the protein. The free hydroxyl group of the hydroxamic acid makes a suboptimal, monodentate complex with the zinc, and strategies for improved inhibitor design can be deduced from the structure. Taken together, the three crystal structures provide the molecular basis for the divergent pharmacological profiles of LTA4 hydrolase inhibitors. Moreover, they help define the binding pocket for the fatty acid-derived epoxide LTA4 as well as the subsites for a tripeptide substrate, which in turn have important implications for the molecular mechanisms of enzyme catalyses.
| + | The line below this paragraph, {{ABSTRACT_PUBMED_12207002}}, adds the Publication Abstract to the page |
| | + | (as it appears on PubMed at http://www.pubmed.gov), where 12207002 is the PubMed ID number. |
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| | + | {{ABSTRACT_PUBMED_12207002}} |
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| | ==About this Structure== | | ==About this Structure== |
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| | [[Category: Protease]] | | [[Category: Protease]] |
| | [[Category: Zinc]] | | [[Category: Zinc]] |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 18:55:27 2008'' | + | |
| | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jul 28 15:18:09 2008'' |
Revision as of 12:18, 28 July 2008
Template:STRUCTURE 2vj8
COMPLEX OF HUMAN LEUKOTRIENE A4 HYDROLASE WITH A HYDROXAMIC ACID INHIBITOR
Template:ABSTRACT PUBMED 12207002
About this Structure
2VJ8 is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Crystal structures of leukotriene A4 hydrolase in complex with captopril and two competitive tight-binding inhibitors., Thunnissen MM, Andersson B, Samuelsson B, Wong CH, Haeggstrom JZ, FASEB J. 2002 Oct;16(12):1648-50. Epub 2002 Aug 7. PMID:12207002
Page seeded by OCA on Mon Jul 28 15:18:09 2008
