Crystal structures of the Toxoplasma gondii hypoxanthine-guanine phosphoribosyltransferase-GMP and -IMP complexes: Comparison of purine binding interactions with the XMP complex

The crystal structures of the guanosine 5'-monophosphate (GMP) and inosine 5'-monophosphate (LMP) complexes of Toxoplasma gondii hypoxanthine-guanine phosphoribosyltransferase (HGPRT) have been determined at 1.65 and 1.90 Ang strom resolution. These complexes, which crystallize in space groups P2(1) (a = 65.45 Angstrom, b = 90.84 Angstrom, c = 80.26 Angstrom, and beta = 92. 53 degrees) and P2(1)2(1)2(1) (a = 84.54 Angstrom, b = 102.44 Angstrom, and 108.83 Angstrom), each comprise a tetramer in the crystallographic asymmet ric unit. All active sites in the tetramers are fully occupied by the nucle otide. Comparison of these structures with that of the xanthosine 5'-monoph osphate (XMP)-pyrophosphate-Mg2+ ternary complex reported in the following article [Heroux, A., et al. (1999) Biochemistry 38, 14495-14506] shows how T. gondii HGPRT is able to recognize guanine, hypoxanthine, and xanthine as substrates, and suggests why the human enzyme cannot use xanthine efficien tly. Comparison with the apoenzyme reveals the structural changes that occu r upon binding of purines and ribose 5'-phosphate to HGPRT. Two structural features important to the HGPRT mechanism, a previously unrecognized active site loop (loop III', residues 180-184) and an active site peptide bond (L eu78-Lys79) that adopts both the cis and the trans configurations, are pres ented.