1bd4
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UPRT-URACIL COMPLEX
OverviewOverview
Uracil phosphoribosyltransferase (UPRTase) catalyzes the transfer of a, ribosyl phosphate group from alpha-D-5-phosphoribosyl-1-pyrophosphate to, the N1 nitrogen of uracil. The UPRTase from the opportunistic pathogen, Toxoplasma gondii is a rational target for antiparasitic drug design. To, aid in structure-based drug design studies against toxoplasmosis, the, crystal structures of the T.gondii apo UPRTase (1.93 A resolution), the, UPRTase bound to its substrate, uracil (2.2 A resolution), its product, UMP (2.5 A resolution), and the prodrug, 5-fluorouracil (2.3 A, resolution), have been determined. These structures reveal that UPRTase, recognizes uracil through polypeptide backbone hydrogen bonds to the, uracil exocyclic O2 and endocyclic N3 atoms and a backbone-water-exocyclic, O4 oxygen hydrogen bond. This stereochemical arrangement and the, architecture of the uracil-binding pocket reveal why cytosine and, pyrimidines with exocyclic substituents at ring position 5 larger than, fluorine, including thymine, cannot bind to the enzyme. Strikingly, the T., gondii UPRTase contains a 22 residue insertion within the conserved PRTase, fold that forms an extended antiparallel beta-arm. Leu92, at the tip of, this arm, functions to cap the active site of its dimer mate, thereby, inhibiting the escape of the substrate-binding water molecule.
About this StructureAbout this Structure
1BD4 is a Single protein structure of sequence from Toxoplasma gondii with PO4 and URA as ligands. Active as Uracil phosphoribosyltransferase, with EC number 2.4.2.9 Full crystallographic information is available from OCA.
ReferenceReference
Crystal structures of Toxoplasma gondii uracil phosphoribosyltransferase reveal the atomic basis of pyrimidine discrimination and prodrug binding., Schumacher MA, Carter D, Scott DM, Roos DS, Ullman B, Brennan RG, EMBO J. 1998 Jun 15;17(12):3219-32. PMID:9628859
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