CRYSTAL-STRUCTURE OF THE HYPOXANTHINE-GUANINE-XANTHINE PHOSPHORIBOSYLTRANSFERASE FROM THE PROTOZOAN PARASITE TRITRICHOMONAS-FETUS

The crystal structure of the hypoxanthine-guanine-xanthine phosphoribo syltransferase (HGXPRTase) from Tritrichomonas foetus has been determi ned and refined against X-ray data to 1.9 Angstrom resolution. T. foet us HGXPRTase crystallizes as an asymmetric dimer, with GMP bound to on ly one of the two molecules that form the asymmetric unit. Each molecu le of HGXPRTase is formed by two lobes joined by a short ''hinge'' reg ion, and the GMP binds in a cavity between the two lobes. A comparison of the two molecules in the asymmetric unit shows that the hinge regi on is flexible and that ligand binding affects the relative positions of the two lobes. The binding of GMP brings the two lobes closer toget her, rotating one lobe by about 5 degrees relative to the other. T. fo etus appears to depend on HGXPRTase for its supply of GMP, making this enzyme a target for antiparasite drug design. A comparison of the str uctures of T. foetus HGXPRTase and human HGPRTase reveals that, while these enzymes retain a similar polypeptide fold, there are substantial differences between the active sites of these two homologs. These dif ferences suggest that it will be possible to find compounds that selec tively inhibit the parasite enzyme.