Journal article
Glutathione transferase P1-1 as an arsenic drug-sequestering enzyme
LJ Parker, A Bocedi, DB Ascher, JB Aitken, HH Harris, M Lo Bello, G Ricci, CJ Morton, MW Parker
Protein Science | WILEY | Published : 2017
DOI: 10.1002/pro.3084
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 sit..
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Funding Acknowledgements
Grant sponsors: Commonwealth of Australia under the Major National Research Facilities Program (Australian Synchrotron Research Program), U.S. DOE, Basic Energy Sciences, Office of Energy Research (Use of the Advanced Photon Source), Australian Research Council (financial support), High Energy Accelerator Research Organization (KEK) in Tsukuba, Japan (operations support), Research Council (ARC), the Australian Cancer Research Foundation (to M.W.P.), the Victorian Government Operational Infrastructure Support Scheme to St. Vincent's Institute and from MIUR and Genesys SpA (to M.L.B.), National Health and Medical Research Council of Australia (NHMRC), Dora Lush Scholarship, and International Centre for Diffraction Data Crystallography Scholarship (to L.J.P.), Australian Postgraduate Award and St Vincent's Foundation Scholarship (to D.B.A.).