1UPU

STRUCTURE OF THE URACIL PHOSPHORIBOSYLTRANSFERASE, MUTANT C128V, BOUND TO PRODUCT URIDINE-1-MONOPHOSPHATE (UMP)

Summary for 1UPU

• Entry DOI: 10.2210/pdb1upu/pdb
• Descriptor: URACIL PHOSPHORIBOSYLTRANSFERASE, PHOSPHATE ION, URIDINE-5'-MONOPHOSPHATE, ... (4 entities in total)
• Functional Keywords: transferase, glycosyltransferase, phosphoribosyltransferase
• Biological source: Toxoplasma gondii
• Total number of polymer chains: 4
• Total formula weight: 103848.66

Authors

Schumacher, M.A.,Carter, D.,Scott, D.,Roos, D.,Ullman, B.,Brennan, R.G. (deposition date: 1998-04-16, release date: 1999-05-11, Last modification date: 2024-02-14)

Primary citation

Schumacher, M.A.,Carter, D.,Scott, D.M.,Roos, D.S.,Ullman, B.,Brennan, R.G.
Crystal structures of Toxoplasma gondii uracil phosphoribosyltransferase reveal the atomic basis of pyrimidine discrimination and prodrug binding.
EMBO J., 17:3219-3232, 1998

PubMed Abstract: 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.

PubMed: 9628859
DOI: 10.1093/emboj/17.12.3219

Experimental method

X-RAY DIFFRACTION (2.5 Å)