2vj8
From Proteopedia
(New page: 200px<br /><applet load="2vj8" size="350" color="white" frame="true" align="right" spinBox="true" caption="2vj8, resolution 1.8Å" /> '''COMPLEX OF HUMAN LEUK...) |
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==Overview== | ==Overview== | ||
| - | Leukotriene (LT) A4 hydrolase/aminopeptidase is a bifunctional zinc enzyme | + | 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. |
==About this Structure== | ==About this Structure== | ||
| - | 2VJ8 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=ZN:'>ZN</scene>, <scene name='pdbligand=YB:'>YB</scene>, <scene name='pdbligand=ACT:'>ACT</scene>, <scene name='pdbligand=IMD:'>IMD</scene> and <scene name='pdbligand=HA2:'>HA2</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Leukotriene-A(4)_hydrolase Leukotriene-A(4) hydrolase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.3.2.6 3.3.2.6] Known structural/functional Sites: <scene name='pdbsite=AC1:Zn Binding Site For Chain A'>AC1</scene>, <scene name='pdbsite=AC2:Yb Binding Site For Chain A'>AC2</scene>, <scene name='pdbsite=AC3:Yb Binding Site For Chain A'>AC3</scene>, <scene name='pdbsite=AC4:Yb Binding Site For Chain A'>AC4</scene>, <scene name='pdbsite=AC5:Imd Binding Site For Chain A'>AC5</scene>, <scene name='pdbsite=AC6:Act Binding Site For Chain A'>AC6</scene> and <scene name='pdbsite=AC7:Ha2 Binding Site For Chain A'>AC7</scene>. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2VJ8 OCA]. | + | 2VJ8 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=ZN:'>ZN</scene>, <scene name='pdbligand=YB:'>YB</scene>, <scene name='pdbligand=ACT:'>ACT</scene>, <scene name='pdbligand=IMD:'>IMD</scene> and <scene name='pdbligand=HA2:'>HA2</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Leukotriene-A(4)_hydrolase Leukotriene-A(4) hydrolase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.3.2.6 3.3.2.6] Known structural/functional Sites: <scene name='pdbsite=AC1:Zn+Binding+Site+For+Chain+A'>AC1</scene>, <scene name='pdbsite=AC2:Yb+Binding+Site+For+Chain+A'>AC2</scene>, <scene name='pdbsite=AC3:Yb+Binding+Site+For+Chain+A'>AC3</scene>, <scene name='pdbsite=AC4:Yb+Binding+Site+For+Chain+A'>AC4</scene>, <scene name='pdbsite=AC5:Imd+Binding+Site+For+Chain+A'>AC5</scene>, <scene name='pdbsite=AC6:Act+Binding+Site+For+Chain+A'>AC6</scene> and <scene name='pdbsite=AC7:Ha2+Binding+Site+For+Chain+A'>AC7</scene>. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2VJ8 OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Andersson, B.]] | [[Category: Andersson, B.]] | ||
| - | [[Category: Haeggstrom, J | + | [[Category: Haeggstrom, J Z.]] |
[[Category: Samuelsson, B.]] | [[Category: Samuelsson, B.]] | ||
| - | [[Category: Thunnissen, M | + | [[Category: Thunnissen, M M.G M.]] |
| - | [[Category: Wong, C | + | [[Category: Wong, C H.]] |
[[Category: ACT]] | [[Category: ACT]] | ||
[[Category: HA2]] | [[Category: HA2]] | ||
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[[Category: zinc]] | [[Category: zinc]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 18:56:22 2008'' |
Revision as of 16:56, 21 February 2008
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COMPLEX OF HUMAN LEUKOTRIENE A4 HYDROLASE WITH A HYDROXAMIC ACID INHIBITOR
Overview
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.
About this Structure
2VJ8 is a Single protein structure of sequence from Homo sapiens with , , , and as ligands. Active as Leukotriene-A(4) hydrolase, with EC number 3.3.2.6 Known structural/functional Sites: , , , , , and . 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 Thu Feb 21 18:56:22 2008
Categories: Homo sapiens | Leukotriene-A(4) hydrolase | Single protein | Andersson, B. | Haeggstrom, J Z. | Samuelsson, B. | Thunnissen, M M.G M. | Wong, C H. | ACT | HA2 | IMD | YB | ZN | Hydrolase | Hydroxamic acid | Leukotriene hydrolase | Metalloprotease | Protease | Zinc
