5n3w

From Proteopedia

(Difference between revisions)

Revision as of 13:47, 29 March 2017

Crystal structure of LTA4H bound to a selective inhibitor against LTB4 generation

Structural highlights

5n3w 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, 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]

Publication Abstract from PubMed

The pro-inflammatory mediator leukotriene B4 (LTB4) is implicated in the pathologies of an array of diseases and thus represents an attractive therapeutic target. The enzyme leukotriene A4 hydrolase (LTA4H) catalyses the distal step in LTB4 synthesis and hence inhibitors of this enzyme have been actively pursued. Despite potent LTA4H inhibitors entering clinical trials all have failed to show efficacy. We recently identified a secondary anti-inflammatory role for LTA4H in degrading the neutrophil chemoattractant Pro-Gly-Pro (PGP) and rationalized that the failure of conventional LTA4H inhibitors may be that they inadvertently prevented PGP degradation. We demonstrate that these inhibitors do indeed fail to discriminate between the dual activities of LTA4H, and enable PGP accumulation in mice. Accordingly, we have developed novel compounds that potently inhibit LTB4 generation whilst leaving PGP degradation unperturbed. These novel compounds could represent a safer and superior class of LTA4H inhibitors for translation into the clinic.

The development of novel LTA4H modulators to selectively target LTB4 generation.,Low CM, Akthar S, Patel DF, Loser S, Wong CT, Jackson PL, Blalock JE, Hare SA, Lloyd CM, Snelgrove RJ Sci Rep. 2017 Mar 17;7:44449. doi: 10.1038/srep44449. PMID:28303931^[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
↑ Low CM, Akthar S, Patel DF, Loser S, Wong CT, Jackson PL, Blalock JE, Hare SA, Lloyd CM, Snelgrove RJ. The development of novel LTA4H modulators to selectively target LTB4 generation. Sci Rep. 2017 Mar 17;7:44449. doi: 10.1038/srep44449. PMID:28303931 doi:http://dx.doi.org/10.1038/srep44449

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/5n3w"

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 5n3w is ON HOLD  until Paper Publication
+==Crystal structure of LTA4H bound to a selective inhibitor against LTB4 generation==
+<StructureSection load='5n3w' size='340' side='right' caption='[[5n3w]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[5n3w]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5N3W OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5N3W FirstGlance]. <br>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=8KW:3-[2-(2-HYDROXYPHENYL)ETHYL]-5-METHOXY-PHENOL'>8KW</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='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=5n3w FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5n3w OCA], [http://pdbe.org/5n3w PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5n3w RCSB], [http://www.ebi.ac.uk/pdbsum/5n3w PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5n3w ProSAT]</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 pro-inflammatory mediator leukotriene B4 (LTB4) is implicated in the pathologies of an array of diseases and thus represents an attractive therapeutic target. The enzyme leukotriene A4 hydrolase (LTA4H) catalyses the distal step in LTB4 synthesis and hence inhibitors of this enzyme have been actively pursued. Despite potent LTA4H inhibitors entering clinical trials all have failed to show efficacy. We recently identified a secondary anti-inflammatory role for LTA4H in degrading the neutrophil chemoattractant Pro-Gly-Pro (PGP) and rationalized that the failure of conventional LTA4H inhibitors may be that they inadvertently prevented PGP degradation. We demonstrate that these inhibitors do indeed fail to discriminate between the dual activities of LTA4H, and enable PGP accumulation in mice. Accordingly, we have developed novel compounds that potently inhibit LTB4 generation whilst leaving PGP degradation unperturbed. These novel compounds could represent a safer and superior class of LTA4H inhibitors for translation into the clinic.
-Authors: Wong, C.T., Low, C.M., Snelgrove, R.J., Hare, S.A.
+The development of novel LTA4H modulators to selectively target LTB4 generation.,Low CM, Akthar S, Patel DF, Loser S, Wong CT, Jackson PL, Blalock JE, Hare SA, Lloyd CM, Snelgrove RJ Sci Rep. 2017 Mar 17;7:44449. doi: 10.1038/srep44449. PMID:28303931<ref>PMID:28303931</ref>
-Description: Crystal structure of LTA4H bound to a selective inhibitor against LTB4 generation
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: Low, C.M]]
+<div class="pdbe-citations 5n3w" style="background-color:#fffaf0;"></div>
-[[Category: Hare, S.A]]
+== References ==
-[[Category: Wong, C.T]]
+<references/>
-[[Category: Snelgrove, R.J]]
+__TOC__
+</StructureSection>
+[[Category: Hare, S A]]
+[[Category: Low, C M]]
+[[Category: Snelgrove, R J]]
+[[Category: Wong, C T]]
+[[Category: Hydrolase]]
+[[Category: Inflammation]]

5n3w

From Proteopedia

Revision as of 13:47, 29 March 2017

Crystal structure of LTA4H bound to a selective inhibitor against LTB4 generation

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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