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J Biol Chem, Vol. 274, Issue 36, 25613-25622, September 3, 1999

The High Resolution Crystal Structure of Recombinant Crithidia fasciculata Tryparedoxin-I

Magnus S. Alphey, Gordon A. Leonard^§, David G. Gourley, Emmanuel Tetaud^¶, Alan H. Fairlamb, and William N. Hunter

From the  Department of Biochemistry, The Wellcome Trust Building, University of Dundee, Dundee, DD1 5EH, Scotland, United Kingdom, ^§ Joint Structural Biology Group, European Synchrotron Radiation Facility, BP 220, F38043, Grenoble, CEDEX, France, ^¶ Laboratoire de Parasitologie Moleculaire, Université Victor Ségalen, Bordeaux II, UPRESA-CNRS 5016, 146, Rue Léo Saignat, F33076 Bordeaux, CEDEX, France

Tryparedoxin-I is a recently discovered thiol-disulfide oxidoreductase involved in the regulation of oxidative stress in parasitic trypanosomatids. The crystal structure of recombinant Crithidia fasciculata tryparedoxin-I in the oxidized state has been determined using multi-wavelength anomalous dispersion methods applied to a selenomethionyl derivative. The model comprises residues 3 to 145 with 236 water molecules and has been refined using all data between a 19- and 1.4-Å resolution to an R-factor and R-free of 19.1 and 22.3%, respectively. Despite sharing only about 20% sequence identity, tryparedoxin-I presents a five-stranded twisted -sheet and two elements of helical structure in the same type of fold as displayed by thioredoxin, the archetypal thiol-disulfide oxidoreductase. However, the relationship of secondary structure with the linear amino acid sequences is different for each protein, producing a distinctive topology. The -sheet core is extended in the trypanosomatid protein with an N-terminal -hairpin. There are also differences in the content and orientation of helical elements of secondary structure positioned at the surface of the proteins, which leads to different shapes and charge distributions between human thioredoxin and tryparedoxin-I. A right-handed redox-active disulfide is formed between Cys-40 and Cys-43 at the N-terminal region of a distorted -helix (1). Cys-40 is solvent-accessible, and Cys-43 is positioned in a hydrophilic cavity. Three C-H···O hydrogen bonds donated from two proline residues serve to stabilize the disulfide-carrying helix and support the correct alignment of active site residues. The accurate model for tryparedoxin-I allows for comparisons with the family of thiol-disulfide oxidoreductases and provides a template for the discovery or design of selective inhibitors of hydroperoxide metabolism in trypanosomes. Such inhibitors are sought as potential therapies against a range of human pathogens.

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