Crystal structure of the hypoxanthine-guanine-xanthine phosphoribosyltransferase from the protozoan parasite Tritrichomonas foetus.
The crystal structure of the hypoxanthine-guanine-xanthine phosphoribosyltransferase (HGXPRTase) from Tritrichomonas foetus has been determined and refined against X-ray data to 1.9 A resolution. T. foetus HGXPRTase crystallizes as an asymmetric dimer, with GMP bound to only one of the two molecules that form the asymmetric unit. Each molecule of HGXPRTase is formed by two lobes joined by a short "hinge" region, 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 region is flexible and that ligand binding affects the relative positions of the two lobes. The binding of GMP brings the two lobes closer together, rotating one lobe by about 5 degrees relative to the other. T. foetus appears to depend on HGXPRTase for its supply of GMP, making this enzyme a target for antiparasite drug design. A comparison of the structures 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 differences suggest that it will be possible to find compounds that selectively inhibit the parasite enzyme.
Somoza
J R
JR
Department of Biochemistry and Biophysics, University of California, San Francisco 94143-0448, USA.
Chin
M S
MS
Focia
P J
PJ
Wang
C C
CC
Fletterick
R J
RJ
D000595:Amino Acid Sequence; D000818:Animals; D000981:Antiprotozoal Agents / Q000494:pharmacology; D001665:Binding Sites; D018360:Crystallography, X-Ray; D015195:Drug Design; D006157:Guanosine Monophosphate / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D007041:Hypoxanthine Phosphoribosyltransferase / Q000737:chemistry; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010430:Pentosyltransferases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D015800:Protozoan Proteins / Q000737:chemistry; D016415:Sequence Alignment; D013379:Substrate Specificity; D016835:Tritrichomonas foetus / Q000201:enzymology*
D000981:Antiprotozoal Agents; D015800:Protozoan Proteins; D006157:Guanosine Monophosphate; D010430:Pentosyltransferases; C083867:hypoxanthine-guanine-xanthine phosphoribosyltransferase; D007041:Hypoxanthine Phosphoribosyltransferase