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dc.contributor.authorParker, L.-
dc.contributor.authorBocedi, A.-
dc.contributor.authorAscher, D.-
dc.contributor.authorAitken, J.-
dc.contributor.authorHarris, H.-
dc.contributor.authorLo Bello, M.-
dc.contributor.authorRicci, G.-
dc.contributor.authorMorton, C.-
dc.contributor.authorParker, M.-
dc.identifier.citationProtein Science, 2017; 26(2):317-326-
dc.description.abstractArsenic-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 A ° , and causes a dramatic widening of the dimer interface by approximately 10 A ° . The GSH conjugate of PAO, which forms rapidly in cancerous cells, is a potent inhibitor (Ki590 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.-
dc.description.statementofresponsibilityLorien J. Parker, Alessio Bocedi, David B. Ascher, Jade B. Aitken, Hugh H. Harris, Mario Lo Bello, Giorgio Ricci, Craig J. Morton and Michael W. Parker-
dc.rights© 2016 The Protein Society-
dc.subjectarsenic; glutathione transferases; inhibitors; resistance; X-ray crystallography-
dc.titleGlutathione transferase P1-1 as an arsenic drug-sequestering enzyme-
dc.typeJournal article-
dc.identifier.orcidHarris, H. [0000-0002-3472-8628]-
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