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| | <StructureSection load='2ht9' size='340' side='right'caption='[[2ht9]], [[Resolution|resolution]] 1.90Å' scene=''> | | <StructureSection load='2ht9' size='340' side='right'caption='[[2ht9]], [[Resolution|resolution]] 1.90Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[2ht9]] 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=2HT9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2HT9 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[2ht9]] 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=2HT9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2HT9 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FES:FE2/S2+(INORGANIC)+CLUSTER'>FES</scene>, <scene name='pdbligand=GSH:GLUTATHIONE'>GSH</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]] 1.9Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">GLRX2 ([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=FES:FE2/S2+(INORGANIC)+CLUSTER'>FES</scene>, <scene name='pdbligand=GSH:GLUTATHIONE'>GSH</scene></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=2ht9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2ht9 OCA], [https://pdbe.org/2ht9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2ht9 RCSB], [https://www.ebi.ac.uk/pdbsum/2ht9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2ht9 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=2ht9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2ht9 OCA], [https://pdbe.org/2ht9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2ht9 RCSB], [https://www.ebi.ac.uk/pdbsum/2ht9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2ht9 ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[https://www.uniprot.org/uniprot/GLRX2_HUMAN GLRX2_HUMAN]] Glutathione-dependent oxidoreductase that facilitates the maintenance of mitochondrial redox homeostasis upon induction of apoptosis by oxidative stress. Involved in response to hydrogen peroxide and regulation of apoptosis caused by oxidative stress. Acts as a very efficient catalyst of monothiol reactions because of its high affinity for protein glutathione-mixed disulfides. Can receive electrons not only from glutathione (GSH), but also from thioredoxin reductase supporting both monothiol and dithiol reactions. Efficiently catalyzes both glutathionylation and deglutathionylation of mitochondrial complex I, which in turn regulates the superoxide production by the complex. Overexpression decreases the susceptibility to apoptosis and prevents loss of cardiolipin and cytochrome c release.<ref>PMID:11297543</ref> <ref>PMID:14676218</ref> <ref>PMID:15328416</ref> <ref>PMID:15649413</ref>
| + | [https://www.uniprot.org/uniprot/GLRX2_HUMAN GLRX2_HUMAN] Glutathione-dependent oxidoreductase that facilitates the maintenance of mitochondrial redox homeostasis upon induction of apoptosis by oxidative stress. Involved in response to hydrogen peroxide and regulation of apoptosis caused by oxidative stress. Acts as a very efficient catalyst of monothiol reactions because of its high affinity for protein glutathione-mixed disulfides. Can receive electrons not only from glutathione (GSH), but also from thioredoxin reductase supporting both monothiol and dithiol reactions. Efficiently catalyzes both glutathionylation and deglutathionylation of mitochondrial complex I, which in turn regulates the superoxide production by the complex. Overexpression decreases the susceptibility to apoptosis and prevents loss of cardiolipin and cytochrome c release.<ref>PMID:11297543</ref> <ref>PMID:14676218</ref> <ref>PMID:15328416</ref> <ref>PMID:15649413</ref> |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Arrowsmith, C]] | + | [[Category: Arrowsmith C]] |
| - | [[Category: Debreczeni, J]] | + | [[Category: Debreczeni J]] |
| - | [[Category: Delft, F von]]
| + | [[Category: Edwards A]] |
| - | [[Category: Edwards, A]] | + | [[Category: Gileadi O]] |
| - | [[Category: Gileadi, O]] | + | [[Category: Johansson C]] |
| - | [[Category: Johansson, C]] | + | [[Category: Kavanagh KL]] |
| - | [[Category: Kavanagh, K L]] | + | [[Category: Oppermann U]] |
| - | [[Category: Oppermann, U]] | + | [[Category: Smee C]] |
| - | [[Category: Structural genomic]]
| + | [[Category: Sundstrom M]] |
| - | [[Category: Smee, C]] | + | [[Category: Weigelt J]] |
| - | [[Category: Sundstrom, M]] | + | [[Category: Von Delft F]] |
| - | [[Category: Weigelt, J]] | + | |
| - | [[Category: Iron-sulfur cluster]] | + | |
| - | [[Category: Oxidoreductase]]
| + | |
| - | [[Category: Sgc]]
| + | |
| - | [[Category: Thioredoxin fold]]
| + | |
| Structural highlights
Function
GLRX2_HUMAN Glutathione-dependent oxidoreductase that facilitates the maintenance of mitochondrial redox homeostasis upon induction of apoptosis by oxidative stress. Involved in response to hydrogen peroxide and regulation of apoptosis caused by oxidative stress. Acts as a very efficient catalyst of monothiol reactions because of its high affinity for protein glutathione-mixed disulfides. Can receive electrons not only from glutathione (GSH), but also from thioredoxin reductase supporting both monothiol and dithiol reactions. Efficiently catalyzes both glutathionylation and deglutathionylation of mitochondrial complex I, which in turn regulates the superoxide production by the complex. Overexpression decreases the susceptibility to apoptosis and prevents loss of cardiolipin and cytochrome c release.[1] [2] [3] [4]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Human mitochondrial glutaredoxin 2 (GLRX2), which controls intracellular redox balance and apoptosis, exists in a dynamic equilibrium of enzymatically active monomers and quiescent dimers. Crystal structures of both monomeric and dimeric forms of human GLRX2 reveal a distinct glutathione binding mode and show a 2Fe-2S-bridged dimer. The iron-sulfur cluster is coordinated through the N-terminal active site cysteine, Cys-37, and reduced glutathione. The structures indicate that the enzyme can be inhibited by a high GSH/GSSG ratio either by forming a 2Fe-2S-bridged dimer that locks away the N-terminal active site cysteine or by binding non-covalently and blocking the active site as seen in the monomer. The properties that permit GLRX2, and not other glutaredoxins, to form an iron-sulfur-containing dimer are likely due to the proline-to-serine substitution in the active site motif, allowing the main chain more flexibility in this area and providing polar interaction with the stabilizing glutathione. This appears to be a novel use of an iron-sulfur cluster in which binding of the cluster inactivates the protein by sequestering active site residues and where loss of the cluster through changes in subcellular redox status creates a catalytically active protein. Under oxidizing conditions, the dimers would readily separate into iron-free active monomers, providing a structural explanation for glutaredoxin activation under oxidative stress.
Reversible sequestration of active site cysteines in a 2Fe-2S-bridged dimer provides a mechanism for glutaredoxin 2 regulation in human mitochondria.,Johansson C, Kavanagh KL, Gileadi O, Oppermann U J Biol Chem. 2007 Feb 2;282(5):3077-82. Epub 2006 Nov 22. PMID:17121859[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Lundberg M, Johansson C, Chandra J, Enoksson M, Jacobsson G, Ljung J, Johansson M, Holmgren A. Cloning and expression of a novel human glutaredoxin (Grx2) with mitochondrial and nuclear isoforms. J Biol Chem. 2001 Jul 13;276(28):26269-75. Epub 2001 Apr 10. PMID:11297543 doi:http://dx.doi.org/10.1074/jbc.M011605200
- ↑ Johansson C, Lillig CH, Holmgren A. Human mitochondrial glutaredoxin reduces S-glutathionylated proteins with high affinity accepting electrons from either glutathione or thioredoxin reductase. J Biol Chem. 2004 Feb 27;279(9):7537-43. Epub 2003 Dec 4. PMID:14676218 doi:http://dx.doi.org/10.1074/jbc.M312719200
- ↑ Lillig CH, Lonn ME, Enoksson M, Fernandes AP, Holmgren A. Short interfering RNA-mediated silencing of glutaredoxin 2 increases the sensitivity of HeLa cells toward doxorubicin and phenylarsine oxide. Proc Natl Acad Sci U S A. 2004 Sep 7;101(36):13227-32. Epub 2004 Aug 24. PMID:15328416 doi:http://dx.doi.org/10.1073/pnas.0401896101
- ↑ Enoksson M, Fernandes AP, Prast S, Lillig CH, Holmgren A, Orrenius S. Overexpression of glutaredoxin 2 attenuates apoptosis by preventing cytochrome c release. Biochem Biophys Res Commun. 2005 Feb 18;327(3):774-9. PMID:15649413 doi:http://dx.doi.org/10.1016/j.bbrc.2004.12.067
- ↑ Johansson C, Kavanagh KL, Gileadi O, Oppermann U. Reversible sequestration of active site cysteines in a 2Fe-2S-bridged dimer provides a mechanism for glutaredoxin 2 regulation in human mitochondria. J Biol Chem. 2007 Feb 2;282(5):3077-82. Epub 2006 Nov 22. PMID:17121859 doi:http://dx.doi.org/10.1074/jbc.M608179200
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