title: Glutathione transferase P1-1 as an arsenic drug-sequestering enzyme.
abstract: Arsenic-based compounds are paradoxically both poisons and drugs. Glutathione transferase (GSTP1-1) is a major factor in resistance to such drugs. Here we describe using crystallography, X-ray absorption spectroscopy, mutagenesis, mass spectrometry, and kinetic studies how GSTP1-1 recognizes the drug phenylarsine oxide (PAO). In conditions of cellular stress where glutathione (GSH) levels are low, PAO crosslinks C47 to C101 of the opposing monomer, a distance of 19.9 Å, and causes a dramatic widening of the dimer interface by approximately 10 Å. The GSH conjugate of PAO, which forms rapidly in cancerous cells, is a potent inhibitor (Ki= 90 nM) and binds as a di-GSH complex in the active site forming part of a continuous network of interactions from one active site to the other. In summary, GSTP1-1 can detoxify arsenic-based drugs by sequestration at the active site and at the dimer interface, in situations where there is a plentiful supply of GSH, and at the reactive cysteines in conditions of low GSH.
authors.affiliation: ACRF Rational Drug Discovery Centre, St. Vincent's Institute of Medical Research, Fitzroy, Victoria, 3065, Australia.|Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria, 3010, Australia.
authors.forename: Lorien J
authors.identifier: 0000-0002-3101-1138
authors.initials: LJ
authors.lastname: Parker
authors.affiliation: Department of Chemical Sciences and Technologies, University of Rome "Tor Vergata", Rome, 00133, Italy.
authors.forename: Alessio
authors.initials: A
authors.lastname: Bocedi
authors.affiliation: ACRF Rational Drug Discovery Centre, St. Vincent's Institute of Medical Research, Fitzroy, Victoria, 3065, Australia.
authors.forename: David B
authors.initials: DB
authors.lastname: Ascher
authors.affiliation: School of Chemistry, The University of Sydney, Sydney, New South Wales, 2006, Australia.
authors.forename: Jade B
authors.initials: JB
authors.lastname: Aitken
authors.affiliation: Department of Chemistry, The University of Adelaide, Adelaide, South Australia, 5005, Australia.
authors.forename: Hugh H
authors.initials: HH
authors.lastname: Harris
authors.affiliation: Department of Biology, University of Rome "Tor Vergata", Rome, 00133, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Lo Bello
authors.affiliation: Department of Chemical Sciences and Technologies, University of Rome "Tor Vergata", Rome, 00133, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Ricci
authors.affiliation: ACRF Rational Drug Discovery Centre, St. Vincent's Institute of Medical Research, Fitzroy, Victoria, 3065, Australia.
authors.forename: Craig J
authors.initials: CJ
authors.lastname: Morton
authors.affiliation: ACRF Rational Drug Discovery Centre, St. Vincent's Institute of Medical Research, Fitzroy, Victoria, 3065, Australia.|Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria, 3010, Australia.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Parker
mesh_terms: D001151:Arsenic / Q000737:chemistry*; D001152:Arsenicals / Q000737:chemistry*; D003432:Cross-Linking Reagents / Q000737:chemistry*; D051549:Glutathione S-Transferase pi / Q000737:chemistry*; D006801:Humans; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary
chemical_list: D001152:Arsenicals; D003432:Cross-Linking Reagents; C029341:oxophenylarsine; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi; D001151:Arsenic
keywords: X-ray crystallography; arsenic; glutathione transferases; inhibitors; resistance