3OZG

Crystal Structure of Plasmodium falciparum Hypoxanthine-Guanine-Xanthine Phosphoribosyltransferase in complex with S-SerMe-ImmH phosphonate

Summary for 3OZG

• Entry DOI: 10.2210/pdb3ozg/pdb
• Related: 3OZF
• Descriptor: Hypoxanthine-guanine-xanthine phosphoribosyltransferase, [(3S)-4-hydroxy-3-{[(4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-7-yl)methyl]amino}butyl]phosphonic acid, PYROPHOSPHATE 2-, ... (5 entities in total)
• Functional Keywords: hypoxanthine, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Plasmodium falciparum FCR-3/Gambia
• Cellular location: Cytoplasm: P20035
• Total number of polymer chains: 4
• Total formula weight: 115708.84

Authors

Ho, M.,Hazleton, K.Z.,Almo, S.C.,Schramm, V.L. (deposition date: 2010-09-24, release date: 2011-09-28, Last modification date: 2023-09-06)

Primary citation

Hazleton, K.Z.,Ho, M.C.,Cassera, M.B.,Clinch, K.,Crump, D.R.,Rosario, I.,Merino, E.F.,Almo, S.C.,Tyler, P.C.,Schramm, V.L.
Acyclic Immucillin Phosphonates: Second-Generation Inhibitors of Plasmodium falciparum Hypoxanthine- Guanine-Xanthine Phosphoribosyltransferase.
Chem.Biol., 19:721-730, 2012

PubMed Abstract: Plasmodium falciparum, the primary cause of deaths from malaria, is a purine auxotroph and relies on hypoxanthine salvage from the host purine pool. Purine starvation as an antimalarial target has been validated by inhibition of purine nucleoside phosphorylase. Hypoxanthine depletion kills Plasmodium falciparum in cell culture and in Aotus monkey infections. Hypoxanthine-guanine-xanthine phosphoribosyltransferase (HGXPRT) from P. falciparum is required for hypoxanthine salvage by forming inosine 5'-monophosphate, a branchpoint for all purine nucleotide synthesis in the parasite. Here, we present a class of HGXPRT inhibitors, the acyclic immucillin phosphonates (AIPs), and cell permeable AIP prodrugs. The AIPs are simple, potent, selective, and biologically stable inhibitors. The AIP prodrugs block proliferation of cultured parasites by inhibiting the incorporation of hypoxanthine into the parasite nucleotide pool and validates HGXPRT as a target in malaria.

PubMed: 22726686
DOI: 10.1016/j.chembiol.2012.04.012

Experimental method

X-RAY DIFFRACTION (1.993 Å)