Structural highlights
7tux is a 4 chain structure with sequence from Plasmodium falciparum. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
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| Method: | X-ray diffraction, Resolution 1.62Å |
| Ligands: | , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
HGXR_PLAFG Converts guanine to guanosine monophosphate, and hypoxanthine to inosine monophosphate. Transfers the 5-phosphoribosyl group from 5-phosphoribosylpyrophosphate onto the purine. Works with guanine, hypoxanthine and xanthine. Plays a central role in the generation of purine nucleotides through the purine salvage pathway.
Publication Abstract from PubMed
Plasmodium falciparum hypoxanthine-guanine-xanthine phosphoribosyltransferase (PfHGXPRT) is essential for purine salvage of hypoxanthine into parasite purine nucleotides. Transition state analogue inhibitors of PfHGXPRT are characterized by kinetic analysis, thermodynamic parameters, and X-ray crystal structures. Compound 1, 9-deazaguanine linked to an acyclic ribocation phosphonate mimic, shows a kinetic K(i) of 0.5 nM. Isothermal titration calorimetry (ITC) experiments of 1 binding to PfHGXPRT reveal enthalpically driven binding with negative cooperativity for the binding of two inhibitor molecules in the tetrameric enzyme. Crystal structures of 1 bound to PfHGXPRT define the hydrogen bond and ionic contacts to complement binding thermodynamics. Dynamics of ribosyl transfer from 5-phospho-alpha-d-ribosyl 1-pyrophosphate (PRPP) to hypoxanthine were examined by (18)O isotope exchange at the bridging phosphoryl oxygen of PRPP pyrophosphate. Rotational constraints or short transition state lifetimes prevent torsional rotation and positional isotope exchange of bridging to nonbridging oxygen in the alpha-pyrophosphoryl group. Thermodynamic analysis of the transition state analogue and magnesium pyrophosphate binding reveal random and cooperative binding to PfHGXPRT, unlike the obligatory ordered reaction kinetics reported earlier for substrate kinetics.
Inhibition and Mechanism of Plasmodium falciparum Hypoxanthine-Guanine-Xanthine Phosphoribosyltransferase.,V T Minnow Y, Suthagar K, Clinch K, Ducati RG, Ghosh A, Buckler JN, Harijan RK, Cahill SM, Tyler PC, Schramm VL ACS Chem Biol. 2022 Nov 22. doi: 10.1021/acschembio.2c00546. PMID:36413975[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ V T Minnow Y, Suthagar K, Clinch K, Ducati RG, Ghosh A, Buckler JN, Harijan RK, Cahill SM, Tyler PC, Schramm VL. Inhibition and Mechanism of Plasmodium falciparum Hypoxanthine-Guanine-Xanthine Phosphoribosyltransferase. ACS Chem Biol. 2022 Nov 22. doi: 10.1021/acschembio.2c00546. PMID:36413975 doi:http://dx.doi.org/10.1021/acschembio.2c00546
