3fh5: Difference between revisions

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-{{Seed}}
-[[Image:3fh5.png|left|200px]]
-<!--
+==Leukotriene A4 Hydrolase complexed with inhibitor (2R)-2-[(4-benzylphenoxy)methyl]pyrrolidine.==
-The line below this paragraph, containing "STRUCTURE_3fh5", creates the "Structure Box" on the page.
+<StructureSection load='3fh5' size='340' side='right'caption='[[3fh5]], [[Resolution|resolution]] 1.63&Aring;' scene=''>
-You may change the PDB parameter (which sets the PDB file loaded into the applet)
+== Structural highlights ==
-or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
+<table><tr><td colspan='2'>[[3fh5]] 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=3FH5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3FH5 FirstGlance]. <br>
-or leave the SCENE parameter empty for the default display.
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.63&#8491;</td></tr>
--->
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=24P:(2R)-2-[(4-BENZYLPHENOXY)METHYL]PYRROLIDINE'>24P</scene>, <scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</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>
-{{STRUCTURE_3fh5|  PDB=3fh5  |  SCENE=  }}
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3fh5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3fh5 OCA], [https://pdbe.org/3fh5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3fh5 RCSB], [https://www.ebi.ac.uk/pdbsum/3fh5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3fh5 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>
+== Evolutionary Conservation ==
+[[Image:Consurf_key_small.gif|200px|right]]
+Check<jmol>
+  <jmolCheckbox>
+    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/fh/3fh5_consurf.spt"</scriptWhenChecked>
+    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
+    <text>to colour the structure by Evolutionary Conservation</text>
+  </jmolCheckbox>
+</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=3fh5 ConSurf].
+<div style="clear:both"></div>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Both in-house human genetic and literature data have converged on the identification of leukotriene 4 hydrolase (LTA(4)H) as a key target for the treatment of cardiovascular disease. We combined fragment-based crystallography screening with an iterative medicinal chemistry effort to optimize inhibitors of LTA(4)H. Ligand efficiency was followed throughout our structure-activity studies. As applied within the context of LTA(4)H inhibitor design, the chemistry team was able to design a potent compound 20 (DG-051) (K(d) = 26 nM) with high aqueous solubility (&gt;30 mg/mL) and high oral bioavailability (&gt;80% across species) that is currently undergoing clinical evaluation for the treatment of myocardial infarction and stroke. The structural biology-chemistry interaction described in this paper provides a sound alternative to conventional screening techniques. This is the first example of a gene-to-clinic paradigm enabled by a fragment-based drug discovery effort.
-===Leukotriene A4 Hydrolase complexed with inhibitor (2R)-2-[(4-benzylphenoxy)methyl]pyrrolidine.===
+Discovery of 4-[(2S)-2-{[4-(4-Chlorophenoxy)phenoxy]methyl}-1-pyrrolidinyl]butanoic Acid (DG-051) as a Novel Leukotriene A4 Hydrolase Inhibitor of Leukotriene B4 Biosynthesis.,Sandanayaka V, Mamat B, Mishra RK, Winger J, Krohn M, Zhou LM, Keyvan M, Enache L, Sullins D, Onua E, Zhang J, Halldorsdottir G, Sigthorsdottir H, Thorlaksdottir A, Sigthorsson G, Thorsteinnsdottir M, Davies DR, Stewart LJ, Zembower DE, Andresson T, Kiselyov AS, Singh J, Gurney ME J Med Chem. 2009 Dec 1. PMID:19950900<ref>PMID:19950900</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 3fh5" style="background-color:#fffaf0;"></div>
-<!--
+==See Also==
-The line below this paragraph, {{ABSTRACT_PUBMED_19950900}}, adds the Publication Abstract to the page
+*[[Leukotriene A4 Hydrolase|Leukotriene A4 Hydrolase]]
-(as it appears on PubMed at http://www.pubmed.gov), where 19950900 is the PubMed ID number.
+== References ==
--->
+<references/>
-{{ABSTRACT_PUBMED_19950900}}
+__TOC__
+</StructureSection>
-==About this Structure==
-FH5 is a 1 chain structure with 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=3FH5 OCA].
-==Reference==
-<ref group="xtra">PMID:19950900</ref><references group="xtra"/>
 [[Category: Homo sapiens]]
-[[Category: Davies, D R.]]
+[[Category: Large Structures]]
-[[Category: Mamat, B.]]
+[[Category: Davies DR]]
-[[Category: Hydrolase-hydrolase inhibitor complex]]
+[[Category: Mamat B]]
-[[Category: Leukotriene a4]]
-[[Category: Leukotriene b4 biosynthesis]]
-[[Category: Leukotriene biosynthesis]]
-[[Category: Lta4h]]
-[[Category: Metal-binding]]
-[[Category: Metalloprotease]]
-[[Category: Multifunctional enzyme]]
-[[Category: Peptidase]]
-[[Category: Protease]]
-[[Category: Structure based drug design]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Aug 18 11:05:37 2010''