3H4K

Crystal structure of the wild type Thioredoxin glutatione reductase from Schistosoma mansoni in complex with auranofin

Summary for 3H4K

• Entry DOI: 10.2210/pdb3h4k/pdb
• Related: 2v6o
• Descriptor: Thioredoxin glutathione reductase, FLAVIN-ADENINE DINUCLEOTIDE, GOLD ION, ... (7 entities in total)
• Functional Keywords: schistosoma mansoni, gold, auranofin, glutathione, fad, flavoprotein, oxidoreductase, redox-active center
• Biological source: Schistosoma mansoni (Blood fluke)
• Total number of polymer chains: 1
• Total formula weight: 67219.37

Authors

Angelucci, F.,Dimastrogiovanni, D.,Miele, A.E.,Boumis, G.,Brunori, M.,Bellelli, A. (deposition date: 2009-04-20, release date: 2009-08-25, Last modification date: 2023-11-01)

Primary citation

Angelucci, F.,Sayed, A.A.,Williams, D.L.,Boumis, G.,Brunori, M.,Dimastrogiovanni, D.,Miele, A.E.,Pauly, F.,Bellelli, A.
Inhibition of Schistosoma mansoni thioredoxin-glutathione reductase by auranofin: structural and kinetic aspects.
J.Biol.Chem., 284:28977-28985, 2009

PubMed Abstract: Schistosomiasis is a parasitic disease affecting over 200 million people currently treated with one drug, praziquantel. A possible drug target is the seleno-protein thioredoxin-glutathione reductase (TGR), a key enzyme in the pathway of the parasite for detoxification of reactive oxygen species. The enzyme is a unique fusion of a glutaredoxin domain with a thioredoxin reductase domain, which contains a selenocysteine (Sec) as the penultimate amino acid. Auranofin (AF), a gold-containing compound already in clinical use as an anti-arthritic drug, has been shown to inhibit TGR and to substantially reduce worm burden in mice. Using x-ray crystallography we solved (at 2.5 A resolution) the structure of wild type TGR incubated with AF. The electron density maps show that the actual inhibitor is gold, released from AF. Gold is bound at three different sites not directly involving the C-terminal Sec residue; however, because the C terminus in the electron density maps is disordered, we cannot exclude the possibility that gold may also bind to Sec. To investigate the possible role of Sec in the inactivation kinetics, we tested the effect of AF on a model enzyme of the same superfamily, i.e. the naturally Sec-lacking glutathione reductase, and on truncated TGR. We demonstrate that the role of selenium in the onset of inhibition by AF is catalytic and can be mimicked by an external source of selenium (benzeneselenol). Therefore, we propose that Sec mediates the transfer of gold from its ligands in AF to the redox-active Cys couples of TGR.

PubMed: 19710012
DOI: 10.1074/jbc.M109.020701

Experimental method

X-RAY DIFFRACTION (2.55 Å)