2gss
From Proteopedia
(New page: 200px<br /> <applet load="2gss" size="450" color="white" frame="true" align="right" spinBox="true" caption="2gss, resolution 1.9Å" /> '''HUMAN GLUTATHIONE S-...) |
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| - | [[Image:2gss.gif|left|200px]]<br /> | + | [[Image:2gss.gif|left|200px]]<br /><applet load="2gss" size="350" color="white" frame="true" align="right" spinBox="true" |
| - | <applet load="2gss" size=" | + | |
caption="2gss, resolution 1.9Å" /> | caption="2gss, resolution 1.9Å" /> | ||
'''HUMAN GLUTATHIONE S-TRANSFERASE P1-1 IN COMPLEX WITH ETHACRYNIC ACID'''<br /> | '''HUMAN GLUTATHIONE S-TRANSFERASE P1-1 IN COMPLEX WITH ETHACRYNIC ACID'''<br /> | ||
==Overview== | ==Overview== | ||
| - | The potent diuretic drug ethacrynic acid has been tested in clinical | + | 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. |
==About this Structure== | ==About this Structure== | ||
| - | 2GSS is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with SO4, EAA and MES as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [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] Full crystallographic information is available from [http:// | + | 2GSS is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=SO4:'>SO4</scene>, <scene name='pdbligand=EAA:'>EAA</scene> and <scene name='pdbligand=MES:'>MES</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [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] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2GSS OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Oakley, A | + | [[Category: Oakley, A J.]] |
| - | [[Category: Parker, M | + | [[Category: Parker, M W.]] |
[[Category: Rossjohn, J.]] | [[Category: Rossjohn, J.]] | ||
[[Category: EAA]] | [[Category: EAA]] | ||
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[[Category: transferase]] | [[Category: transferase]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 17:35:00 2008'' |
Revision as of 15:35, 21 February 2008
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HUMAN GLUTATHIONE S-TRANSFERASE P1-1 IN COMPLEX WITH ETHACRYNIC ACID
Overview
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.
About this Structure
2GSS is a Single protein structure of sequence from Homo sapiens with , and as ligands. Active as Glutathione transferase, with EC number 2.5.1.18 Full crystallographic information is available from OCA.
Reference
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
Page seeded by OCA on Thu Feb 21 17:35:00 2008
Categories: Glutathione transferase | Homo sapiens | Single protein | Oakley, A J. | Parker, M W. | Rossjohn, J. | EAA | MES | SO4 | Detoxification | Ethacrynic acid | Glutathione | Pi | Transferase
