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{{STRUCTURE_4ms6|  PDB=4ms6  |  SCENE=  }}
===Human Leukotriene A4 Hydrolase in complex with Pro-Gly-Pro analogue===
{{ABSTRACT_PUBMED_24591641}}


==Function==
==Human Leukotriene A4 Hydrolase in complex with Pro-Gly-Pro analogue==
[[http://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>
<StructureSection load='4ms6' size='340' side='right'caption='[[4ms6]], [[Resolution|resolution]] 1.72&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4ms6]] 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=4MS6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4MS6 FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.72&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=28T:1-{4-OXO-4-[(2S)-PYRROLIDIN-2-YL]BUTANOYL}-L-PROLINE'>28T</scene>, <scene name='pdbligand=ACY:ACETIC+ACID'>ACY</scene>, <scene name='pdbligand=YB:YTTERBIUM+(III)+ION'>YB</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4ms6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ms6 OCA], [https://pdbe.org/4ms6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4ms6 RCSB], [https://www.ebi.ac.uk/pdbsum/4ms6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4ms6 ProSAT]</span></td></tr>
</table>
== Function ==
[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>  
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Leukotriene (LT) A4 hydrolase/aminopeptidase (LTA4H) is a bifunctional zinc metalloenzyme that catalyzes the committed step in the formation of the proinflammatory mediator LTB4. Recently, the chemotactic tripeptide Pro-Gly-Pro was identified as an endogenous aminopeptidase substrate for LTA4 hydrolase. Here, we determined the crystal structure of LTA4 hydrolase in complex with a Pro-Gly-Pro analog at 1.72 A. From the structure, which includes the catalytic water, and mass spectrometric analysis of enzymatic hydrolysis products of Pro-Gly-Pro, it could be inferred that LTA4 hydrolase cleaves at the N terminus of the palindromic tripeptide. Furthermore, we designed a small molecule, 4-(4-benzylphenyl)thiazol-2-amine, denoted ARM1, that inhibits LTB4 synthesis in human neutrophils (IC50 of approximately 0.5 muM) and conversion of LTA4 into LTB4 by purified LTA4H with a Ki of 2.3 muM. In contrast, 50- to 100-fold higher concentrations of ARM1 did not significantly affect hydrolysis of Pro-Gly-Pro. A 1.62-A crystal structure of LTA4 hydrolase in a dual complex with ARM1 and the Pro-Gly-Pro analog revealed that ARM1 binds in the hydrophobic pocket that accommodates the omega-end of LTA4, distant from the aminopeptidase active site, thus providing a molecular basis for its inhibitory profile. Hence, ARM1 selectively blocks conversion of LTA4 into LTB4, although sparing the enzyme's anti-inflammatory aminopeptidase activity (i.e., degradation and inactivation of Pro-Gly-Pro). ARM1 represents a new class of LTA4 hydrolase inhibitor that holds promise for improved anti-inflammatory properties.


==About this Structure==
Binding of Pro-Gly-Pro at the active site of leukotriene A4 hydrolase/aminopeptidase and development of an epoxide hydrolase selective inhibitor.,Stsiapanava A, Olsson U, Wan M, Kleinschmidt T, Rutishauser D, Zubarev RA, Samuelsson B, Rinaldo-Matthis A, Haeggstrom JZ Proc Natl Acad Sci U S A. 2014 Mar 3. PMID:24591641<ref>PMID:24591641</ref>
[[4ms6]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4MS6 OCA].


==Reference==
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
<ref group="xtra">PMID:024591641</ref><references group="xtra"/><references/>
</div>
[[Category: Haeggstrom, J Z.]]
<div class="pdbe-citations 4ms6" style="background-color:#fffaf0;"></div>
[[Category: Rinaldo-Matthis, A.]]
 
[[Category: Stsiapanava, A.]]
==See Also==
[[Category: Hydrolase]]
*[[Leukotriene A4 Hydrolase|Leukotriene A4 Hydrolase]]
[[Category: Leukotriene a4 hydrolase]]
== References ==
[[Category: Metalloprotein]]
<references/>
[[Category: Protease]]
__TOC__
[[Category: Zinc binding]]
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Haeggstrom JZ]]
[[Category: Rinaldo-Matthis A]]
[[Category: Stsiapanava A]]
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