1fsg
TOXOPLASMA GONDII HYPOXANTHINE-GUANINE PHOSPHORIBOSYLTRANSFERASE COMPLEXED WITH 9-DEAZAGUANINE, ALPHA-D-5-PHOSPHORIBOSYL-1-PYROPHOSPHATE (PRPP) AND TWO MG2+ IONS
OverviewOverview
BACKGROUND: Hypoxanthine-guanine phosphoribosyltransferases (HGPRTs) are well-recognized antiparasitic drug targets. HGPRT is also a paradigmatic representative of the phosphoribosyltransferase family of enzymes, which includes other important biosynthetic and salvage enzymes and drug targets. To better understand the reaction mechanism of this enzyme, we have crystallized HGPRT from the apicomplexan protozoan Toxoplasma gondii as a ternary complex with a substrate and a substrate analog. RESULTS: The crystal structure of T. gondii HGPRT with the substrate Mg2+-PRPP and a nonreactive substrate analog, 9-deazaguanine, bound in the active site has been determined at 1.05 A resolution and refined to a free R factor of 15.4%. This structure constitutes the first atomic-resolution structure of both a phosphoribosyltransferase and the central metabolic substrate PRPP. This pre-transition state complex provides a clearer understanding of the structural basis for catalysis by HGPRT. CONCLUSIONS: Three types of substrate deformation, chief among them an unexpected C2'-endo pucker adopted by the PRPP ribose ring, raise the energy of the ground state. A cation-pi interaction between Tyr-118 and the developing oxocarbenium ion in the ribose ring helps to stabilize the transition state. Enforced substrate propinquity coupled with optimal reactive geometry for both the substrates and the active site residues with which they interact contributes to catalysis as well.
About this StructureAbout this Structure
1FSG is a Single protein structure of sequence from Toxoplasma gondii. Full crystallographic information is available from OCA.
ReferenceReference
Substrate deformation in a hypoxanthine-guanine phosphoribosyltransferase ternary complex: the structural basis for catalysis., Heroux A, White EL, Ross LJ, Kuzin AP, Borhani DW, Structure. 2000 Dec 15;8(12):1309-18. PMID:11188695 Page seeded by OCA on Fri May 2 16:42:45 2008