1gw6

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[[Image:1gw6.gif|left|200px]]<br />
 
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<applet load="1gw6" size="450" color="white" frame="true" align="right" spinBox="true"
 
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caption="1gw6, resolution 2.20&Aring;" />
 
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'''STRUCTURE OF LEUKOTRIENE A4 HYDROLASE D375N MUTANT'''<br />
 
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==Overview==
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==STRUCTURE OF LEUKOTRIENE A4 HYDROLASE D375N MUTANT==
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Leukotriene A4 (LTA4, 5S-trans-5,6-oxido-7,9-trans-11,14-cis-eicosatetraenoic acid) hydrolase, (LTA4H)/aminopeptidase is a bifunctional zinc metalloenzyme that catalyzes, the final and rate-limiting step in the biosynthesis of leukotriene B4, (LTB4, 5S,12R-dihydroxy-6,14-cis-8,10-trans-eicosatetraenoic acid), a, classical chemoattractant and immune modulating lipid mediator. Two, chemical features are key to the bioactivity of LTB4, namely, the, chirality of the 12R-hydroxyl group and the cis-trans-trans geometry of, the conjugated triene structure. From the crystal structure of LTA4H, a, hydrophilic patch composed of Gln-134, Tyr-267, and Asp-375 was identified, in a narrow and otherwise hydrophobic pocket, believed to bind LTA4. In, addition, Asp-375 belongs to peptide K21, a previously characterized, 21-residue active site-peptide to which LTA4 binds during suicide, inactivation. In the present report we used site-directed mutagenesis and, x-ray crystallography to show that Asp-375, but none of the other, candidate residues, is specifically required for the epoxide hydrolase, activity of LTA4H. Thus, mutation of Asp-375 leads to a selective loss of, the enzyme's ability to generate LTB4 whereas the aminopeptidase activity, is preserved. We propose that Asp-375, possibly assisted by Gln-134, acts, as a critical determinant for the stereoselective introduction of the, 12R-hydroxyl group and thus the biological activity of LTB4.
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<StructureSection load='1gw6' size='340' side='right'caption='[[1gw6]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[1gw6]] 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=1GW6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1GW6 FirstGlance]. <br>
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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]] 2.2&#8491;</td></tr>
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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=BES:2-(3-AMINO-2-HYDROXY-4-PHENYL-BUTYRYLAMINO)-4-METHYL-PENTANOIC+ACID'>BES</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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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1gw6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1gw6 OCA], [https://pdbe.org/1gw6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1gw6 RCSB], [https://www.ebi.ac.uk/pdbsum/1gw6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1gw6 ProSAT]</span></td></tr>
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</table>
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== Function ==
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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/gw/1gw6_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=1gw6 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 A4 (LTA4, 5S-trans-5,6-oxido-7,9-trans-11,14-cis-eicosatetraenoic acid) hydrolase (LTA4H)/aminopeptidase is a bifunctional zinc metalloenzyme that catalyzes the final and rate-limiting step in the biosynthesis of leukotriene B4 (LTB4, 5S,12R-dihydroxy-6,14-cis-8,10-trans-eicosatetraenoic acid), a classical chemoattractant and immune modulating lipid mediator. Two chemical features are key to the bioactivity of LTB4, namely, the chirality of the 12R-hydroxyl group and the cis-trans-trans geometry of the conjugated triene structure. From the crystal structure of LTA4H, a hydrophilic patch composed of Gln-134, Tyr-267, and Asp-375 was identified in a narrow and otherwise hydrophobic pocket, believed to bind LTA4. In addition, Asp-375 belongs to peptide K21, a previously characterized 21-residue active site-peptide to which LTA4 binds during suicide inactivation. In the present report we used site-directed mutagenesis and x-ray crystallography to show that Asp-375, but none of the other candidate residues, is specifically required for the epoxide hydrolase activity of LTA4H. Thus, mutation of Asp-375 leads to a selective loss of the enzyme's ability to generate LTB4 whereas the aminopeptidase activity is preserved. We propose that Asp-375, possibly assisted by Gln-134, acts as a critical determinant for the stereoselective introduction of the 12R-hydroxyl group and thus the biological activity of LTB4.
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==About this Structure==
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Leukotriene A4 hydrolase: selective abrogation of leukotriene B4 formation by mutation of aspartic acid 375.,Rudberg PC, Tholander F, Thunnissen MM, Samuelsson B, Haeggstrom JZ Proc Natl Acad Sci U S A. 2002 Apr 2;99(7):4215-20. Epub 2002 Mar 26. PMID:11917124<ref>PMID:11917124</ref>
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1GW6 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 ACT, YB, ZN, BES and IMD 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] Structure known Active Site: BES. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1GW6 OCA].
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==Reference==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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Leukotriene A4 hydrolase: selective abrogation of leukotriene B4 formation by mutation of aspartic acid 375., Rudberg PC, Tholander F, Thunnissen MM, Samuelsson B, Haeggstrom JZ, Proc Natl Acad Sci U S A. 2002 Apr 2;99(7):4215-20. Epub 2002 Mar 26. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=11917124 11917124]
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</div>
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[[Category: Homo sapiens]]
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<div class="pdbe-citations 1gw6" style="background-color:#fffaf0;"></div>
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[[Category: Leukotriene-A(4) hydrolase]]
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[[Category: Single protein]]
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[[Category: Haeggstrom, J.Z.]]
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[[Category: Rudberg, P.C.]]
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[[Category: Samuelsson, B.]]
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[[Category: Tholander, F.]]
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[[Category: Thunnissen, M.M.G.M.]]
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[[Category: ACT]]
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[[Category: BES]]
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[[Category: IMD]]
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[[Category: YB]]
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[[Category: ZN]]
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[[Category: alpha-beta protein]]
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[[Category: hydrolase]]
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[[Category: mutagenesis studies]]
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''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 17:09:42 2007''
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==See Also==
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*[[Leukotriene A4 Hydrolase|Leukotriene A4 Hydrolase]]
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== References ==
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<references/>
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__TOC__
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</StructureSection>
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[[Category: Homo sapiens]]
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[[Category: Large Structures]]
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[[Category: Haeggstrom JZ]]
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[[Category: Rudberg PC]]
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[[Category: Samuelsson B]]
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[[Category: Tholander F]]
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[[Category: Thunnissen MMGM]]

Current revision

STRUCTURE OF LEUKOTRIENE A4 HYDROLASE D375N MUTANT

PDB ID 1gw6

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