2vj8

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[[Image:2vj8.jpg|left|200px]]
 
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{{Structure
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==Complex of human leukotriene A4 hydrolase with a hydroxamic acid inhibitor==
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|PDB= 2vj8 |SIZE=350|CAPTION= <scene name='initialview01'>2vj8</scene>, resolution 1.8&Aring;
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<StructureSection load='2vj8' size='340' side='right'caption='[[2vj8]], [[Resolution|resolution]] 1.80&Aring;' scene=''>
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|SITE= <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>
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== Structural highlights ==
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|LIGAND= <scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=HA2:6-[{(2S)-2-AMINO-3-[4-(BENZYLOXY)PHENYL]PROPYL}(HYDROXY)AMINO]-6-OXOHEXANOIC+ACID)'>HA2</scene>, <scene name='pdbligand=IMD:IMIDAZOLE'>IMD</scene>, <scene name='pdbligand=YB:YTTERBIUM+(III)+ION'>YB</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene>
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<table><tr><td colspan='2'>[[2vj8]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2VJ8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2VJ8 FirstGlance]. <br>
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|ACTIVITY= <span class='plainlinks'>[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] </span>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.8&#8491;</td></tr>
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|GENE=
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=HA2:6-[{(2S)-2-AMINO-3-[4-(BENZYLOXY)PHENYL]PROPYL}(HYDROXY)AMINO]-6-OXOHEXANOIC+ACID)'>HA2</scene>, <scene name='pdbligand=IMD:IMIDAZOLE'>IMD</scene>, <scene name='pdbligand=YB:YTTERBIUM+(III)+ION'>YB</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
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|DOMAIN=
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2vj8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2vj8 OCA], [https://pdbe.org/2vj8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2vj8 RCSB], [https://www.ebi.ac.uk/pdbsum/2vj8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2vj8 ProSAT]</span></td></tr>
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|RELATEDENTRY=
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</table>
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|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2vj8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2vj8 OCA], [http://www.ebi.ac.uk/pdbsum/2vj8 PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2vj8 RCSB]</span>
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== Function ==
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}}
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[https://www.uniprot.org/uniprot/LKHA4_HUMAN LKHA4_HUMAN] Epoxide hydrolase that catalyzes the final step in the biosynthesis of the proinflammatory mediator leukotriene B4. Has also aminopeptidase activity.<ref>PMID:1897988</ref> <ref>PMID:1975494</ref> <ref>PMID:2244921</ref> <ref>PMID:12207002</ref> <ref>PMID:11917124</ref> <ref>PMID:15078870</ref> <ref>PMID:18804029</ref>
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/vj/2vj8_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2vj8 ConSurf].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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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.
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'''COMPLEX OF HUMAN LEUKOTRIENE A4 HYDROLASE WITH A HYDROXAMIC ACID INHIBITOR'''
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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<ref>PMID:12207002</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 2vj8" style="background-color:#fffaf0;"></div>
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==Overview==
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==See Also==
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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.
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*[[Leukotriene A4 Hydrolase|Leukotriene A4 Hydrolase]]
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== References ==
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==About this Structure==
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<references/>
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2VJ8 is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2VJ8 OCA].
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__TOC__
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</StructureSection>
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==Reference==
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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:[http://www.ncbi.nlm.nih.gov/pubmed/12207002 12207002]
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[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Leukotriene-A(4) hydrolase]]
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[[Category: Large Structures]]
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[[Category: Single protein]]
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[[Category: Andersson B]]
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[[Category: Andersson, B.]]
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[[Category: Haeggstrom JZ]]
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[[Category: Haeggstrom, J Z.]]
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[[Category: Samuelsson B]]
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[[Category: Samuelsson, B.]]
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[[Category: Thunnissen MMGM]]
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[[Category: Thunnissen, M M.G M.]]
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[[Category: Wong C-H]]
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[[Category: Wong, C H.]]
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[[Category: hydrolase]]
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[[Category: hydroxamic acid]]
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[[Category: leukotriene hydrolase]]
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[[Category: metalloprotease]]
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[[Category: protease]]
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[[Category: zinc]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 05:13:04 2008''
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Current revision

Complex of human leukotriene A4 hydrolase with a hydroxamic acid inhibitor

PDB ID 2vj8

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