3chp: Difference between revisions

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<StructureSection load='3chp' size='340' side='right'caption='[[3chp]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
<StructureSection load='3chp' size='340' side='right'caption='[[3chp]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[3chp]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3CHP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3CHP FirstGlance]. <br>
<table><tr><td colspan='2'>[[3chp]] 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=3CHP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3CHP FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=4BO:(3S)-3-AMINO-4-OXO-4-[(4-PHENYLMETHOXYPHENYL)AMINO]BUTANOIC+ACID'>4BO</scene>, <scene name='pdbligand=ACT:ACETATE+ION'>ACT</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>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.1&#8491;</td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[1hs6|1hs6]], [[1gw6|1gw6]], [[1h19|1h19]], [[1sqm|1sqm]], [[3cho|3cho]], [[3chq|3chq]], [[3chr|3chr]], [[3chs|3chs]], [[2vj8|2vj8]]</div></td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=4BO:(3S)-3-AMINO-4-OXO-4-[(4-PHENYLMETHOXYPHENYL)AMINO]BUTANOIC+ACID'>4BO</scene>, <scene name='pdbligand=ACT:ACETATE+ION'>ACT</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>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">LTA4H, LTA4 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Leukotriene-A(4)_hydrolase Leukotriene-A(4) hydrolase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.3.2.6 3.3.2.6] </span></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=3chp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3chp OCA], [https://pdbe.org/3chp PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3chp RCSB], [https://www.ebi.ac.uk/pdbsum/3chp PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3chp ProSAT]</span></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=3chp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3chp OCA], [https://pdbe.org/3chp PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3chp RCSB], [https://www.ebi.ac.uk/pdbsum/3chp PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3chp ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== 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>
[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>  
== Evolutionary Conservation ==
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
[[Image:Consurf_key_small.gif|200px|right]]
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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=3chp ConSurf].
</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=3chp ConSurf].
<div style="clear:both"></div>
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Leukotriene B(4) (LTB(4)) is a potent pro-inflammatory mediator that has been implicated in the pathogenesis of multiple diseases, including psoriasis, inflammatory bowel disease, multiple sclerosis and asthma. As a method to decrease the level of LTB(4) and possibly identify novel treatments, inhibitors of the LTB(4) biosynthetic enzyme, leukotriene A(4) hydrolase (LTA(4)-h), have been explored. Here we describe the discovery of a potent inhibitor of LTA(4)-h, arylamide of glutamic acid 4f, starting from the corresponding glycinamide 2. Analogs of 4f are then described, focusing on compounds that are both active and stable in whole blood. This effort culminated in the identification of amino alcohol 12a and amino ester 6b which meet these criteria.
Synthesis of glutamic acid analogs as potent inhibitors of leukotriene A4 hydrolase.,Kirkland TA, Adler M, Bauman JG, Chen M, Haeggstrom JZ, King B, Kochanny MJ, Liang AM, Mendoza L, Phillips GB, Thunnissen M, Trinh L, Whitlow M, Ye B, Ye H, Parkinson J, Guilford WJ Bioorg Med Chem. 2008 May 1;16(9):4963-83. Epub 2008 Mar 20. PMID:18394906<ref>PMID:18394906</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 3chp" style="background-color:#fffaf0;"></div>


==See Also==
==See Also==
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__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Human]]
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Large Structures]]
[[Category: Adler, M]]
[[Category: Adler M]]
[[Category: Thunnissen, M M.G M]]
[[Category: Thunnissen MMGM]]
[[Category: Whitlow, M]]
[[Category: Whitlow M]]
[[Category: Alpha-beta protein]]
[[Category: Alternative splicing]]
[[Category: Cytoplasm]]
[[Category: Epoxide hydrolase]]
[[Category: Hydrolase]]
[[Category: Inhibitor complex]]
[[Category: Leukotriene biosynthesis]]
[[Category: Metal-binding]]
[[Category: Metalloprotease]]
[[Category: Multifunctional enzyme]]
[[Category: Zinc]]

Latest revision as of 12:35, 21 February 2024

Crystal structure of leukotriene a4 hydrolase in complex with (3S)-3-amino-4-oxo-4-[(4-phenylmethoxyphenyl)amino]butanoic acidCrystal structure of leukotriene a4 hydrolase in complex with (3S)-3-amino-4-oxo-4-[(4-phenylmethoxyphenyl)amino]butanoic acid

Structural highlights

3chp is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.1Å
Ligands:, , , ,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

LKHA4_HUMAN Epoxide hydrolase that catalyzes the final step in the biosynthesis of the proinflammatory mediator leukotriene B4. Has also aminopeptidase activity.[1] [2] [3] [4] [5] [6] [7]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

See Also

References

  1. ↑ Odlander B, Claesson HE, Bergman T, Radmark O, Jornvall H, Haeggstrom JZ. Leukotriene A4 hydrolase in the human B-lymphocytic cell line Raji: indications of catalytically divergent forms of the enzyme. Arch Biochem Biophys. 1991 May 15;287(1):167-74. PMID:1897988
  2. ↑ Toh H, Minami M, Shimizu T. Molecular evolution and zinc ion binding motif of leukotriene A4 hydrolase. Biochem Biophys Res Commun. 1990 Aug 31;171(1):216-21. PMID:1975494
  3. ↑ Haeggstrom JZ, Wetterholm A, Shapiro R, Vallee BL, Samuelsson B. Leukotriene A4 hydrolase: a zinc metalloenzyme. Biochem Biophys Res Commun. 1990 Nov 15;172(3):965-70. PMID:2244921
  4. ↑ Thunnissen MM, Andersson B, Samuelsson B, Wong CH, Haeggstrom JZ. Crystal structures of leukotriene A4 hydrolase in complex with captopril and two competitive tight-binding inhibitors. FASEB J. 2002 Oct;16(12):1648-50. Epub 2002 Aug 7. PMID:12207002 doi:10.1096/fj.01-1017fje
  5. ↑ Rudberg PC, Tholander F, Thunnissen MM, Samuelsson B, Haeggstrom JZ. Leukotriene A4 hydrolase: selective abrogation of leukotriene B4 formation by mutation of aspartic acid 375. Proc Natl Acad Sci U S A. 2002 Apr 2;99(7):4215-20. Epub 2002 Mar 26. PMID:11917124 doi:10.1073/pnas.072090099
  6. ↑ Rudberg PC, Tholander F, Andberg M, Thunnissen MM, Haeggstrom JZ. Leukotriene A4 hydrolase: identification of a common carboxylate recognition site for the epoxide hydrolase and aminopeptidase substrates. J Biol Chem. 2004 Jun 25;279(26):27376-82. Epub 2004 Apr 12. PMID:15078870 doi:10.1074/jbc.M401031200
  7. ↑ Tholander F, Muroya A, Roques BP, Fournie-Zaluski MC, Thunnissen MM, Haeggstrom JZ. Structure-based dissection of the active site chemistry of leukotriene A4 hydrolase: implications for M1 aminopeptidases and inhibitor design. Chem Biol. 2008 Sep 22;15(9):920-9. PMID:18804029 doi:10.1016/j.chembiol.2008.07.018

3chp, resolution 2.10Å

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