2GSS
HUMAN GLUTATHIONE S-TRANSFERASE P1-1 IN COMPLEX WITH ETHACRYNIC ACID
Summary for 2GSS
| Entry DOI | 10.2210/pdb2gss/pdb |
| Descriptor | GLUTATHIONE S-TRANSFERASE P1-1, SULFATE ION, ETHACRYNIC ACID, ... (5 entities in total) |
| Functional Keywords | glutathione, transferase, pi, detoxification, ethacrynic acid |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 2 |
| Total formula weight | 47781.19 |
| Authors | Oakley, A.J.,Rossjohn, J.,Parker, M.W. (deposition date: 1996-10-29, release date: 1997-11-12, Last modification date: 2024-05-29) |
| Primary citation | Oakley, A.J.,Rossjohn, J.,Lo Bello, M.,Caccuri, A.M.,Federici, G.,Parker, M.W. 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, 36:576-585, 1997 Cited by PubMed Abstract: 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. PubMed: 9012673DOI: 10.1021/bi962316i PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.9 Å) |
Structure validation
Download full validation report
