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PDBsum entry 3gss
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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The three-Dimensional structure of the human pi class glutathione transferase p1-1 in complex with the inhibitor ethacrynic acid and its glutathione conjugate.
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Authors
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A.J.Oakley,
J.Rossjohn,
M.Lo bello,
A.M.Caccuri,
G.Federici,
M.W.Parker.
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Ref.
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Biochemistry, 1997,
36,
576-585.
[DOI no: ]
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PubMed id
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Abstract
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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.
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Secondary reference #1
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Title
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Three-Dimensional structure of class pi glutathione s-Transferase from human placenta in complex with s-Hexylglutathione at 2.8 a resolution.
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Authors
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P.Reinemer,
H.W.Dirr,
R.Ladenstein,
R.Huber,
M.Lo bello,
G.Federici,
M.W.Parker.
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Ref.
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J Mol Biol, 1992,
227,
214-226.
[DOI no: ]
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PubMed id
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Figure 8.
Figure 8. Conolly dot surface of the op region of human class x glutathione S-transferase showing both active sites
occupied by S-hexyllutathione. View is along the local dyad. Also shown is the cavity formed between the 2 subunits.
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Figure 9.
Figure 9. Model o inhibitor S-hexylglutathione and its next neighbors at the active site of human
-transferase.
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The above figures are
reproduced from the cited reference
with permission from Elsevier
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