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| | ==HUMAN GLUTATHIONE S-TRANSFERASE P1-1 IN COMPLEX WITH ETHACRYNIC ACID-GLUTATHIONE CONJUGATE== | | ==HUMAN GLUTATHIONE S-TRANSFERASE P1-1 IN COMPLEX WITH ETHACRYNIC ACID-GLUTATHIONE CONJUGATE== |
| - | <StructureSection load='3gss' size='340' side='right' caption='[[3gss]], [[Resolution|resolution]] 1.90Å' scene=''> | + | <StructureSection load='3gss' size='340' side='right'caption='[[3gss]], [[Resolution|resolution]] 1.90Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3gss]] is a 2 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=3GSS OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3GSS FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3gss]] is a 2 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=3GSS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3GSS FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EAA:ETHACRYNIC+ACID'>EAA</scene>, <scene name='pdbligand=GSH:GLUTATHIONE'>GSH</scene>, <scene name='pdbligand=MES:2-(N-MORPHOLINO)-ETHANESULFONIC+ACID'>MES</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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">GSTP1 ([http://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=EAA:ETHACRYNIC+ACID'>EAA</scene>, <scene name='pdbligand=GSH:GLUTATHIONE'>GSH</scene>, <scene name='pdbligand=MES:2-(N-MORPHOLINO)-ETHANESULFONIC+ACID'>MES</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Glutathione_transferase Glutathione transferase], with EC number [http://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=3gss FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3gss OCA], [https://pdbe.org/3gss PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3gss RCSB], [https://www.ebi.ac.uk/pdbsum/3gss PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3gss 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=3gss FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3gss OCA], [http://pdbe.org/3gss PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3gss RCSB], [http://www.ebi.ac.uk/pdbsum/3gss PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3gss ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/GSTP1_HUMAN GSTP1_HUMAN]] Conjugation of reduced glutathione to a wide number of exogenous and endogenous hydrophobic electrophiles. Regulates negatively CDK5 activity via p25/p35 translocation to prevent neurodegeneration.<ref>PMID:21668448</ref> | + | [https://www.uniprot.org/uniprot/GSTP1_HUMAN GSTP1_HUMAN] Conjugation of reduced glutathione to a wide number of exogenous and endogenous hydrophobic electrophiles. Regulates negatively CDK5 activity via p25/p35 translocation to prevent neurodegeneration.<ref>PMID:21668448</ref> |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
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| | ==See Also== | | ==See Also== |
| - | *[[Glutathione S-transferase|Glutathione S-transferase]] | + | *[[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: Oakley, A J]] | + | [[Category: Oakley AJ]] |
| - | [[Category: Parker, M W]] | + | [[Category: Parker MW]] |
| - | [[Category: Rossjohn, J]] | + | [[Category: Rossjohn J]] |
| - | [[Category: Detoxification]]
| + | |
| - | [[Category: Ethacrynic acid]]
| + | |
| - | [[Category: Glutathione]]
| + | |
| - | [[Category: Pi]]
| + | |
| - | [[Category: Transferase]]
| + | |
| Structural highlights
Function
GSTP1_HUMAN Conjugation of reduced glutathione to a wide number of exogenous and endogenous hydrophobic electrophiles. Regulates negatively CDK5 activity via p25/p35 translocation to prevent neurodegeneration.[1]
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
The potent diuretic drug ethacrynic acid has been tested in clinical trials as an adjuvant in chemotherapy. Its target is the detoxifying enzyme glutathione transferase which is often found overexpressed in cancer tissues. We have solved the crystal structures of human pi class glutathione transferase P1-1 in complex with the inhibitor ethacrynic acid and its glutathione conjugate. Ethacrynic acid is found to bind in a nonproductive mode to one of the ligand binding sites of the enzyme (the H site) while the glutathione binding site (G site) is occupied by solvent molecules. There are no structural rearrangements of the G site in the absence of ligand. The structure indicates that bound glutathione is required for ethacrynic acid to dock into the H site in a productive binding mode. The binding of the ethacrynic acid-glutathione conjugate shows that the contacts of the glutathione moiety with the protein are identical to those observed in crystal structures of the enzyme with other glutathione-based substrates and inhibitors. The ethacrynic acid moiety of the conjugate binds in the H site in a fashion that has not been observed in crystal structures of other glutathione-based inhibitor complexes. The crystal structures implicate Tyr 108 as an electrophilic participant in the Michael addition of glutathione to ethacrynic acid.
The three-dimensional structure of the human Pi class glutathione transferase P1-1 in complex with the inhibitor ethacrynic acid and its glutathione conjugate.,Oakley AJ, Rossjohn J, Lo Bello M, Caccuri AM, Federici G, Parker MW Biochemistry. 1997 Jan 21;36(3):576-85. PMID:9012673[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Sun KH, Chang KH, Clawson S, Ghosh S, Mirzaei H, Regnier F, Shah K. Glutathione-S-transferase P1 is a critical regulator of Cdk5 kinase activity. J Neurochem. 2011 Sep;118(5):902-14. doi: 10.1111/j.1471-4159.2011.07343.x. Epub , 2011 Jul 8. PMID:21668448 doi:10.1111/j.1471-4159.2011.07343.x
- ↑ Oakley AJ, Rossjohn J, Lo Bello M, Caccuri AM, Federici G, Parker MW. The three-dimensional structure of the human Pi class glutathione transferase P1-1 in complex with the inhibitor ethacrynic acid and its glutathione conjugate. Biochemistry. 1997 Jan 21;36(3):576-85. PMID:9012673 doi:http://dx.doi.org/10.1021/bi962316i
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