6ssr

From Proteopedia

(Difference between revisions)

Current revision

Crystal structure of Human Microsomal Glutathione S-Transferase 2 at 3.8 Angstroms resolution

Structural highlights

6ssr is a 3 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 3.8Å
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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.

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

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6ssr"

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 6ssr is ON HOLD  until Paper Publication
+==Crystal structure of Human Microsomal Glutathione S-Transferase 2 at 3.8 Angstroms resolution==
+<StructureSection load='6ssr' size='340' side='right'caption='[[6ssr]], [[Resolution|resolution]] 3.80&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[6ssr]] 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=6SSR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6SSR FirstGlance]. <br>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.8&#8491;</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=6ssr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ssr OCA], [https://pdbe.org/6ssr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6ssr RCSB], [https://www.ebi.ac.uk/pdbsum/6ssr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6ssr ProSAT]</span></td></tr>
+</table>
+== 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>
+<div style="background-color:#fffaf0;">
+== 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.
-Authors:
+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<ref>PMID:33741927</ref>
-Description:
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
+<div class="pdbe-citations 6ssr" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Glutathione S-transferase 3D structures|Glutathione S-transferase 3D structures]]
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Haeggstrom JZ]]
+[[Category: Nji E]]
+[[Category: Rinaldo-Matthis A]]
+[[Category: Thulasingam M]]

6ssr

From Proteopedia

Current revision

Crystal structure of Human Microsomal Glutathione S-Transferase 2 at 3.8 Angstroms resolution

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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