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.

Parker, L.j., Bocedi, A., Ascher, D.b., Aitken, J.b., Harris, H.h., Lo Bello, M., et al. (2017). Glutathione transferase P1-1 as an arsenic drug-sequestering enzyme. PROTEIN SCIENCE, 26(2), 317-326 [10.1002/pro.3084].

Glutathione transferase P1-1 as an arsenic drug-sequestering enzyme

Bocedi A.;Lo Bello M.;Ricci G.;
2017-02-01

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.
feb-2017
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore BIO/10 - BIOCHIMICA
English
X-ray crystallography; arsenic; glutathione transferases; inhibitors; resistance; Arsenic; Arsenicals; Cross-Linking Reagents; Glutathione S-Transferase pi; Humans; Protein Multimerization; Protein Structure, Quaternary
Parker, L.j., Bocedi, A., Ascher, D.b., Aitken, J.b., Harris, H.h., Lo Bello, M., et al. (2017). Glutathione transferase P1-1 as an arsenic drug-sequestering enzyme. PROTEIN SCIENCE, 26(2), 317-326 [10.1002/pro.3084].
Parker, Lj; Bocedi, A; Ascher, Db; Aitken, Jb; Harris, Hh; Lo Bello, M; Ricci, G; Morton, Cj; Parker, Mw
Articolo su rivista
File in questo prodotto:
File Dimensione Formato  
Parker_et_al-2017-Protein_Science.pdf

solo utenti autorizzati

Licenza: Copyright dell'editore
Dimensione 2.19 MB
Formato Adobe PDF
2.19 MB Adobe PDF   Visualizza/Apri   Richiedi una copia

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/215911
Citazioni
  • ???jsp.display-item.citation.pmc??? 3
  • Scopus 19
  • ???jsp.display-item.citation.isi??? 16
social impact