Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/104882
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Type: Journal article
Title: Glutathione transferase P1-1 as an arsenic drug-sequestering enzyme
Author: Parker, L.
Bocedi, A.
Ascher, D.
Aitken, J.
Harris, H.
Lo Bello, M.
Ricci, G.
Morton, C.
Parker, M.
Citation: Protein Science, 2017; 26(2):317-326
Publisher: Wiley
Issue Date: 2017
ISSN: 0961-8368
1469-896X
Statement of
Responsibility: 
Lorien 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
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 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.
Keywords: arsenic; glutathione transferases; inhibitors; resistance; X-ray crystallography
Rights: © 2016 The Protein Society
RMID: 0030059185
DOI: 10.1002/pro.3084
Appears in Collections:Physics publications

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