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| | <StructureSection load='6ssw' size='340' side='right'caption='[[6ssw]], [[Resolution|resolution]] 3.00Å' scene=''> | | <StructureSection load='6ssw' size='340' side='right'caption='[[6ssw]], [[Resolution|resolution]] 3.00Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6ssw]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6SSW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6SSW FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6ssw]] is a 3 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=6SSW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6SSW FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GTS:GLUTATHIONE+SULFONIC+ACID'>GTS</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]] 3Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">MGST2, GST2 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GTS:GLUTATHIONE+SULFONIC+ACID'>GTS</scene></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Glutathione_transferase Glutathione transferase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.5.1.18 2.5.1.18] </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=6ssw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ssw OCA], [https://pdbe.org/6ssw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6ssw RCSB], [https://www.ebi.ac.uk/pdbsum/6ssw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6ssw ProSAT]</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=6ssw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ssw OCA], [https://pdbe.org/6ssw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6ssw RCSB], [https://www.ebi.ac.uk/pdbsum/6ssw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6ssw ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[https://www.uniprot.org/uniprot/MGST2_HUMAN MGST2_HUMAN]] Catalyzes several different glutathione-dependent reactions (PubMed:8703034, PubMed:9278457, PubMed:23409838, PubMed:26656251, PubMed:26066610). Catalyzes the glutathione-dependent reduction of lipid hydroperoxides, such as 5-HPETE (PubMed:9278457, PubMed:23409838). Has glutathione transferase activity, toward xenobiotic electrophiles, such as 1-chloro-2, 4-dinitrobenzene (CDNB) (PubMed:23409838, PubMed:8703034). Catalyzes also the conjugation of leukotriene A4 with reduced glutathione to form leukotriene C4 (LTC4) (PubMed:23409838, PubMed:26656251). Involved in oxidative DNA damage induced by ER stress and anticancer agents by activating LTC4 biosynthetic machinery in nonimmune cells (PubMed:26656251).<ref>PMID:23409838</ref> <ref>PMID:26066610</ref> <ref>PMID:26656251</ref> <ref>PMID:8703034</ref> <ref>PMID:9278457</ref>
| + | [https://www.uniprot.org/uniprot/MGST2_HUMAN MGST2_HUMAN] Catalyzes several different glutathione-dependent reactions (PubMed:8703034, PubMed:9278457, PubMed:23409838, PubMed:26656251, PubMed:26066610). Catalyzes the glutathione-dependent reduction of lipid hydroperoxides, such as 5-HPETE (PubMed:9278457, PubMed:23409838). Has glutathione transferase activity, toward xenobiotic electrophiles, such as 1-chloro-2, 4-dinitrobenzene (CDNB) (PubMed:23409838, PubMed:8703034). Catalyzes also the conjugation of leukotriene A4 with reduced glutathione to form leukotriene C4 (LTC4) (PubMed:23409838, PubMed:26656251). Involved in oxidative DNA damage induced by ER stress and anticancer agents by activating LTC4 biosynthetic machinery in nonimmune cells (PubMed:26656251).<ref>PMID:23409838</ref> <ref>PMID:26066610</ref> <ref>PMID:26656251</ref> <ref>PMID:8703034</ref> <ref>PMID:9278457</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 6ssw" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 6ssw" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Glutathione S-transferase 3D structures|Glutathione S-transferase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Glutathione transferase]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Human]]
| + | |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Haeggstrom, J Z]] | + | [[Category: Haeggstrom JZ]] |
| - | [[Category: Thulasingam, M]] | + | [[Category: Thulasingam M]] |
| - | [[Category: Integral membrane protein]]
| + | |
| - | [[Category: Mapeg]]
| + | |
| - | [[Category: Mgst2]]
| + | |
| - | [[Category: Transferase]]
| + | |
| Structural highlights
Function
MGST2_HUMAN Catalyzes several different glutathione-dependent reactions (PubMed:8703034, PubMed:9278457, PubMed:23409838, PubMed:26656251, PubMed:26066610). Catalyzes the glutathione-dependent reduction of lipid hydroperoxides, such as 5-HPETE (PubMed:9278457, PubMed:23409838). Has glutathione transferase activity, toward xenobiotic electrophiles, such as 1-chloro-2, 4-dinitrobenzene (CDNB) (PubMed:23409838, PubMed:8703034). Catalyzes also the conjugation of leukotriene A4 with reduced glutathione to form leukotriene C4 (LTC4) (PubMed:23409838, PubMed:26656251). Involved in oxidative DNA damage induced by ER stress and anticancer agents by activating LTC4 biosynthetic machinery in nonimmune cells (PubMed:26656251).[1] [2] [3] [4] [5]
Publication Abstract from PubMed
Microsomal glutathione S-transferase 2 (MGST2) produces leukotriene C4, key for intracrine signaling of endoplasmic reticulum (ER) stress, oxidative DNA damage and cell death. MGST2 trimer restricts catalysis to only one out of three active sites at a time, but the molecular basis is unknown. Here, we present crystal structures of human MGST2 combined with biochemical and computational evidence for a concerted mechanism, involving local unfolding coupled to global conformational changes that regulate catalysis. Furthermore, synchronized changes in the biconical central pore modulate the hydrophobicity and control solvent influx to optimize reaction conditions at the active site. These unique mechanistic insights pertain to other, structurally related, drug targets.
Crystal structures of human MGST2 reveal synchronized conformational changes regulating catalysis.,Thulasingam M, Orellana L, Nji E, Ahmad S, Rinaldo-Matthis A, Haeggstrom JZ Nat Commun. 2021 Mar 19;12(1):1728. doi: 10.1038/s41467-021-21924-8. PMID:33741927[6]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Ahmad S, Niegowski D, Wetterholm A, Haeggstrom JZ, Morgenstern R, Rinaldo-Matthis A. Catalytic characterization of human microsomal glutathione S-transferase 2: identification of rate-limiting steps. Biochemistry. 2013 Mar 12;52(10):1755-64. doi: 10.1021/bi3014104. Epub 2013 Feb, 27. PMID:23409838 doi:http://dx.doi.org/10.1021/bi3014104
- ↑ Ahmad S, Thulasingam M, Palombo I, Daley DO, Johnson KA, Morgenstern R, Haeggstrom JZ, Rinaldo-Matthis A. Trimeric microsomal glutathione transferase 2 displays one third of the sites reactivity. Biochim Biophys Acta. 2015 Oct;1854(10 Pt A):1365-71. doi:, 10.1016/j.bbapap.2015.06.003. Epub 2015 Jun 9. PMID:26066610 doi:http://dx.doi.org/10.1016/j.bbapap.2015.06.003
- ↑ Dvash E, Har-Tal M, Barak S, Meir O, Rubinstein M. Leukotriene C4 is the major trigger of stress-induced oxidative DNA damage. Nat Commun. 2015 Dec 11;6:10112. doi: 10.1038/ncomms10112. PMID:26656251 doi:http://dx.doi.org/10.1038/ncomms10112
- ↑ Jakobsson PJ, Mancini JA, Ford-Hutchinson AW. Identification and characterization of a novel human microsomal glutathione S-transferase with leukotriene C4 synthase activity and significant sequence identity to 5-lipoxygenase-activating protein and leukotriene C4 synthase. J Biol Chem. 1996 Sep 6;271(36):22203-10. PMID:8703034
- ↑ Jakobsson PJ, Mancini JA, Riendeau D, Ford-Hutchinson AW. Identification and characterization of a novel microsomal enzyme with glutathione-dependent transferase and peroxidase activities. J Biol Chem. 1997 Sep 5;272(36):22934-9. PMID:9278457
- ↑ Thulasingam M, Orellana L, Nji E, Ahmad S, Rinaldo-Matthis A, Haeggstrom JZ. Crystal structures of human MGST2 reveal synchronized conformational changes regulating catalysis. Nat Commun. 2021 Mar 19;12(1):1728. doi: 10.1038/s41467-021-21924-8. PMID:33741927 doi:http://dx.doi.org/10.1038/s41467-021-21924-8
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