5aen

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(Difference between revisions)

Revision as of 11:48, 12 February 2015

Structure of human Leukotriene A4 hydrolase in complex with inhibitor dimethyl(2- (4-phenoxyphenoxy)ethyl)amine

Structural highlights

5aen is a 1 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, , ,
Activity:	Leukotriene-A(4) hydrolase, with EC number 3.3.2.6
Resources:	FirstGlance, OCA, RCSB, PDBsum

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]

Publication Abstract from PubMed

The pharmacophore concept is commonly employed in virtual screening for hit identification. A pharmacophore is generally defined as the three-dimensional arrangement of the structural and physicochemical features of a compound responsible for its affinity to a pharmacological target. Given a number of active ligands binding to a particular target in the same manner, it can reasonably be assumed that they have some shared features, a common pharmacophore. We present a growing neural gas (GNG)-based approach for the extraction of the relevant features which we called PENG (pharmacophore elucidation by neural gas). Results of retrospective validation indicate an acceptable quality of the generated models. Additionally a prospective virtual screening for leukotriene A4 hydrolase (LTA4H) inhibitors was performed. LTA4H is a bifunctional zinc metalloprotease which displays both epoxide hydrolase and aminopeptidase activity. We could show that the PENG approach is able to predict the binding mode of the ligand by X-ray crystallography. Furthermore, we identified a novel chemotype of LTA4H inhibitors.

PENG: A Neural Gas-Based Approach for Pharmacophore Elucidation. Method Design, Validation, and Virtual Screening for Novel Ligands of LTA4H.,Moser D, Wittmann SK, Kramer J, Blocher R, Achenbach J, Pogoryelov D, Proschak E J Chem Inf Model. 2015 Feb 9. PMID:25625859^[8]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ 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
↑ 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
↑ 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
↑ 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
↑ 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
↑ 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
↑ 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
↑ Moser D, Wittmann SK, Kramer J, Blocher R, Achenbach J, Pogoryelov D, Proschak E. PENG: A Neural Gas-Based Approach for Pharmacophore Elucidation. Method Design, Validation, and Virtual Screening for Novel Ligands of LTA4H. J Chem Inf Model. 2015 Feb 9. PMID:25625859 doi:http://dx.doi.org/10.1021/ci500618u

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5aen"

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
+==Structure of human Leukotriene A4 hydrolase in complex with inhibitor dimethyl(2- (4-phenoxyphenoxy)ethyl)amine==
+<StructureSection load='5aen' size='340' side='right' caption='[[5aen]], [[Resolution|resolution]] 1.86&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[5aen]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5AEN OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5AEN FirstGlance]. <br>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=DP8:N,N-DIMETHYL-2-(4-PHENOXYPHENOXY)ETHANAMINE'>DP8</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='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><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></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5aen FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5aen OCA], [http://www.rcsb.org/pdb/explore.do?structureId=5aen RCSB], [http://www.ebi.ac.uk/pdbsum/5aen PDBsum]</span></td></tr>
+</table>
+== Function ==
+[[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>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+The pharmacophore concept is commonly employed in virtual screening for hit identification. A pharmacophore is generally defined as the three-dimensional arrangement of the structural and physicochemical features of a compound responsible for its affinity to a pharmacological target. Given a number of active ligands binding to a particular target in the same manner, it can reasonably be assumed that they have some shared features, a common pharmacophore. We present a growing neural gas (GNG)-based approach for the extraction of the relevant features which we called PENG (pharmacophore elucidation by neural gas). Results of retrospective validation indicate an acceptable quality of the generated models. Additionally a prospective virtual screening for leukotriene A4 hydrolase (LTA4H) inhibitors was performed. LTA4H is a bifunctional zinc metalloprotease which displays both epoxide hydrolase and aminopeptidase activity. We could show that the PENG approach is able to predict the binding mode of the ligand by X-ray crystallography. Furthermore, we identified a novel chemotype of LTA4H inhibitors.
-The entry 5aen is ON HOLD
+PENG: A Neural Gas-Based Approach for Pharmacophore Elucidation. Method Design, Validation, and Virtual Screening for Novel Ligands of LTA4H.,Moser D, Wittmann SK, Kramer J, Blocher R, Achenbach J, Pogoryelov D, Proschak E J Chem Inf Model. 2015 Feb 9. PMID:25625859<ref>PMID:25625859</ref>
-Authors: Moser, D., Wittmann, S.K., Kramer, J., Blocher, R., Achenbach, J., Pogoryelov, D., Proschak, E.
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
-Description: Structure of human Leukotriene A4 hydrolase in complex with inhibitor dimethyl(2-(4-phenoxyphenoxy)ethyl)amine
+== References ==
-[[Category: Unreleased Structures]]
+<references/>
-[[Category: Proschak, E]]
+__TOC__
+</StructureSection>
+[[Category: Achenbach, J]]
+[[Category: Blocher, R]]
 [[Category: Kramer, J]]
+[[Category: Moser, D]]
 [[Category: Pogoryelov, D]]
-[[Category: Moser, D]]
+[[Category: Proschak, E]]
-[[Category: Achenbach, J]]
+[[Category: Wittmann, S K]]
-[[Category: Blocher, R]]
+[[Category: Hydrolase]]
-[[Category: Wittmann, S.K]]
+[[Category: Lta4h]]

5aen

From Proteopedia

Revision as of 11:48, 12 February 2015

Structure of human Leukotriene A4 hydrolase in complex with inhibitor dimethyl(2- (4-phenoxyphenoxy)ethyl)amine

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

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