1JLR: Structure Of The Uracil Phosphoribosyltransferase Gtp Complex 2 Mutant C128v

Citation:
Abstract
Uracil phosphoribosyltransferase (UPRT) is a member of a large family of salvage and biosynthetic enzymes, the phosphoribosyltransferases, and catalyzes the transfer of ribose 5-phosphate from alpha-d-5-phosphoribosyl-1-pyrophosphate (PRPP) to the N1 nitrogen of uracil. The UPRT from the opportunistic pathogen Toxoplasma gondii represents a promising target for rational drug design, because it can create intracellular, lethal nucleotides from subversive substrates. However, the development of such compounds requires a detailed understanding of the catalytic mechanism. Toward this end we determined the crystal structure of the T. gondii UPRT bound to uracil and cPRPP, a nonhydrolyzable PRPP analogue, to 2.5-A resolution. The structure suggests that the catalytic mechanism is substrate-assisted, and a tetramer would be the more active oligomeric form of the enzyme. Subsequent biochemical studies revealed that GTP binding, which has been suggested to play a role in catalysis by other UPRTs, causes a 6-fold activation of the T. gondii enzyme and strikingly stabilizes the tetramer form. The basis for stabilization was revealed in the 2.45-A resolution structure of the UPRT-GTP complex, whereby residues from three subunits contributed to GTP binding. Thus, our studies reveal an allosteric mechanism involving nucleotide stabilization of a more active, higher order oligomer. Such regulation of UPRT could play a role in the balance of purine and pyrimidine nucleotide pools in the cell.
PDB ID: 1JLRDownload
MMDB ID: 18616
PDB Deposition Date: 2001/7/16
Updated in MMDB: 2017/10
Experimental Method:
x-ray diffraction
Resolution: 2.45  Å
Source Organism:
Similar Structures:
Biological Unit for 1JLR: tetrameric; determined by author and by software (PISA)
Molecular Components in 1JLR
Label Count Molecule
Proteins (4 molecules)
4
Uracil Phosphoribosyltransferase
Molecule annotation
Chemicals (12 molecules)
1
8
2
4
* Click molecule labels to explore molecular sequence information.

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