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| | ==Crystal structure of a human integral membrane enzyme== | | ==Crystal structure of a human integral membrane enzyme== |
| - | <StructureSection load='4bpm' size='340' side='right' caption='[[4bpm]], [[Resolution|resolution]] 2.08Å' scene=''> | + | <StructureSection load='4bpm' size='340' side='right'caption='[[4bpm]], [[Resolution|resolution]] 2.08Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4bpm]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4BPM OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4BPM FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4bpm]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4BPM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4BPM FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GSH:GLUTATHIONE'>GSH</scene>, <scene name='pdbligand=LVJ:2-[[2,6-BIS(CHLORANYL)-3-[(2,2-DIMETHYLPROPANOYLAMINO)METHYL]PHENYL]AMINO]-1-METHYL-6-(2-METHYL-2-OXIDANYL-PROPOXY)-N-[2,2,2-TRIS(FLUORANYL)ETHYL]BENZIMIDAZOLE-5-CARBOXAMIDE'>LVJ</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]] 2.08Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4bpd|4bpd]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GSH:GLUTATHIONE'>GSH</scene>, <scene name='pdbligand=LVJ:2-[[2,6-BIS(CHLORANYL)-3-[(2,2-DIMETHYLPROPANOYLAMINO)METHYL]PHENYL]AMINO]-1-METHYL-6-(2-METHYL-2-OXIDANYL-PROPOXY)-N-[2,2,2-TRIS(FLUORANYL)ETHYL]BENZIMIDAZOLE-5-CARBOXAMIDE'>LVJ</scene></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Prostaglandin-E_synthase Prostaglandin-E synthase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=5.3.99.3 5.3.99.3] </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=4bpm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4bpm OCA], [https://pdbe.org/4bpm PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4bpm RCSB], [https://www.ebi.ac.uk/pdbsum/4bpm PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4bpm ProSAT]</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=4bpm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4bpm OCA], [http://pdbe.org/4bpm PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4bpm RCSB], [http://www.ebi.ac.uk/pdbsum/4bpm PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4bpm ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | + | == Disease == |
| | + | [https://www.uniprot.org/uniprot/LTC4S_HUMAN LTC4S_HUMAN] Defects in LTC4S are the cause of leukotriene C4 synthase deficiency (LTC4 synthase deficiency) [MIM:[https://omim.org/entry/246530 246530]. LTC4 synthase deficiency is a fatal neurometabolic developmental disorder. It is associated with muscular hypotonia, psychomotor retardation, failure to thrive, and microcephaly. |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/PTGES_HUMAN PTGES_HUMAN]] Catalyzes the oxidoreduction of prostaglandin endoperoxide H2 (PGH2) to prostaglandin E2 (PGE2).<ref>PMID:18682561</ref> | + | [https://www.uniprot.org/uniprot/LTC4S_HUMAN LTC4S_HUMAN] Catalyzes the conjugation of leukotriene A4 with reduced glutathione to form leukotriene C4.[https://www.uniprot.org/uniprot/PTGES_HUMAN PTGES_HUMAN] Catalyzes the oxidoreduction of prostaglandin endoperoxide H2 (PGH2) to prostaglandin E2 (PGE2).<ref>PMID:18682561</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Prostaglandin-E synthase]] | + | [[Category: Large Structures]] |
| - | [[Category: Caffrey, M]] | + | [[Category: Synthetic construct]] |
| - | [[Category: Li, D]] | + | [[Category: Caffrey M]] |
| - | [[Category: Olieric, V]] | + | [[Category: Li D]] |
| - | [[Category: Wang, M]] | + | [[Category: Olieric V]] |
| - | [[Category: Anomalous dispersion]]
| + | [[Category: Wang M]] |
| - | [[Category: Cancer]]
| + | |
| - | [[Category: Drug target]]
| + | |
| - | [[Category: In meso crystallization]]
| + | |
| - | [[Category: Inflammation]]
| + | |
| - | [[Category: Inhibitor]]
| + | |
| - | [[Category: Isomerase]]
| + | |
| - | [[Category: Leukotriene c4 synthase]]
| + | |
| - | [[Category: Lipid metabolism]]
| + | |
| - | [[Category: Mapag]]
| + | |
| - | [[Category: Membrane protein]]
| + | |
| - | [[Category: Membrane-associated proteins in eicosanoid and glutathione metabolism]]
| + | |
| - | [[Category: Microcrystal]]
| + | |
| - | [[Category: Mpges1]]
| + | |
| - | [[Category: Pain]]
| + | |
| - | [[Category: S-sad]]
| + | |
| - | [[Category: Sulfur-sad]]
| + | |
| Structural highlights
Disease
LTC4S_HUMAN Defects in LTC4S are the cause of leukotriene C4 synthase deficiency (LTC4 synthase deficiency) [MIM:246530. LTC4 synthase deficiency is a fatal neurometabolic developmental disorder. It is associated with muscular hypotonia, psychomotor retardation, failure to thrive, and microcephaly.
Function
LTC4S_HUMAN Catalyzes the conjugation of leukotriene A4 with reduced glutathione to form leukotriene C4.PTGES_HUMAN Catalyzes the oxidoreduction of prostaglandin endoperoxide H2 (PGH2) to prostaglandin E2 (PGE2).[1]
Publication Abstract from PubMed
The lipidic mesophase or in meso method for crystallizing membrane proteins has several high profile targets to its credit and is growing in popularity. Despite its success, the method is in its infancy as far as rational crystallogenesis is concerned. Consequently, significant time, effort, and resources are still required to generate structure-grade crystals, especially with a new target type. Therefore, a need exists for crystallogenesis protocols that are effective with a broad range of membrane protein types. Recently, a strategy for crystallizing a prokaryotic alpha-helical membrane protein, diacylglycerol kinase (DgkA), by the in meso method was reported (Cryst. Growth. Des.2013, 14, 2846-2857). Here, we describe its application to the human alpha-helical microsomal prostaglandin E2 synthase 1 (mPGES1). While the DgkA strategy proved useful, significant modifications were needed to generate structure-quality crystals of this important therapeutic target. These included protein engineering, using an additive phospholipid in the hosting mesophase, performing multiple rounds of salt screening, and carrying out trials at 4 degrees C in the presence of a tight binding ligand. The crystallization strategy detailed here should prove useful for generating structures of other integral membrane proteins by the in meso method.
Crystallizing Membrane Proteins in the Lipidic Mesophase. Experience with Human Prostaglandin E2 Synthase 1 and an Evolving Strategy.,Li D, Howe N, Dukkipati A, Shah ST, Bax BD, Edge C, Bridges A, Hardwicke P, Singh OM, Giblin G, Pautsch A, Pfau R, Schnapp G, Wang M, Olieric V, Caffrey M Cryst Growth Des. 2014 Apr 2;14(4):2034-2047. Epub 2014 Mar 7. PMID:24803849[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Jegerschold C, Pawelzik SC, Purhonen P, Bhakat P, Gheorghe KR, Gyobu N, Mitsuoka K, Morgenstern R, Jakobsson PJ, Hebert H. Structural basis for induced formation of the inflammatory mediator prostaglandin E2. Proc Natl Acad Sci U S A. 2008 Aug 12;105(32):11110-5. Epub 2008 Aug 5. PMID:18682561 doi:0802894105
- ↑ Li D, Howe N, Dukkipati A, Shah ST, Bax BD, Edge C, Bridges A, Hardwicke P, Singh OM, Giblin G, Pautsch A, Pfau R, Schnapp G, Wang M, Olieric V, Caffrey M. Crystallizing Membrane Proteins in the Lipidic Mesophase. Experience with Human Prostaglandin E2 Synthase 1 and an Evolving Strategy. Cryst Growth Des. 2014 Apr 2;14(4):2034-2047. Epub 2014 Mar 7. PMID:24803849 doi:http://dx.doi.org/10.1021/cg500157x
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