title: Studies of glutathione transferase P1-1 bound to a platinum(IV)-based anticancer compound reveal the molecular basis of its activation.
abstract: Platinum-based cancer drugs, such as cisplatin, are highly effective chemotherapeutic agents used extensively for the treatment of solid tumors. However, their effectiveness is limited by drug resistance, which, in some cancers, has been associated with an overexpression of pi class glutathione S-transferase (GST P1-1), an important enzyme in the mercapturic acid detoxification pathway. Ethacraplatin (EA-CPT), a trans-Pt(IV) carboxylate complex containing ethacrynate ligands, was designed as a platinum cancer metallodrug that could also target cytosolic GST enzymes. We previously reported that EA-CPT was an excellent inhibitor of GST activity in live mammalian cells compared to either cisplatin or ethacrynic acid. In order to understand the nature of the drug-protein interactions between EA-CPT and GST P1-1, and to obtain mechanistic insights at a molecular level, structural and biochemical investigations were carried out, supported by molecular modeling analysis using quantum mechanical/molecular mechanical methods. The results suggest that EA-CPT preferentially docks at the dimer interface at GST P1-1 and subsequent interaction with the enzyme resulted in docking of the ethacrynate ligands at both active sites (in the H-sites), with the Pt moiety remaining bound at the dimer interface. The activation of the inhibitor by its target enzyme and covalent binding accounts for the strong and irreversible inhibition of enzymatic activity by the platinum complex.
authors.affiliation: Biota Structural Biology Laboratory, St. Vincent's Institute of Medical Research, 41 Victoria Parade, Fitzroy, Victoria 3065, Australia.
authors.forename: Lorien J
authors.initials: LJ
authors.lastname: Parker
authors.forename: Louis C
authors.initials: LC
authors.lastname: Italiano
authors.forename: Craig J
authors.initials: CJ
authors.lastname: Morton
authors.forename: Nancy C
authors.initials: NC
authors.lastname: Hancock
authors.forename: David B
authors.initials: DB
authors.lastname: Ascher
authors.forename: Jade B
authors.initials: JB
authors.lastname: Aitken
authors.forename: Hugh H
authors.initials: HH
authors.lastname: Harris
authors.forename: Pablo
authors.initials: P
authors.lastname: Campomanes
authors.forename: Ursula
authors.initials: U
authors.lastname: Rothlisberger
authors.forename: Anastasia
authors.initials: A
authors.lastname: De Luca
authors.forename: Mario
authors.initials: M
authors.lastname: Lo Bello
authors.forename: Wee Han
authors.initials: WH
authors.lastname: Ang
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Dyson
authors.forename: Michael W
authors.initials: MW
authors.lastname: Parker
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism* / Q000627:therapeutic use; D002945:Cisplatin / Q000737:chemistry / Q000627:therapeutic use; D018360:Crystallography, X-Ray; D019281:Dimerization; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D004976:Ethacrynic Acid / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D051549:Glutathione S-Transferase pi / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy; D010984:Platinum / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; D010984:Platinum; D051549:Glutathione S-Transferase pi; D004976:Ethacrynic Acid; D002945:Cisplatin