7SCR

Crystal structure of trypanosome brucei hypoxanthine-guanine-xanthine phosphoribzosyltransferase in complex with (4S,7S)-7-hydroxy-4-((guanin-9-yl)methyl)-2,5-dioxaheptan-1,7-diphosphonate

Summary for 7SCR

• Entry DOI: 10.2210/pdb7scr/pdb
• Descriptor: Hypoxanthine-guanine phosphoribosyltransferase, ({(2S)-3-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)-2-[(2S)-2-hydroxy-2-phosphonoethoxy]propoxy}methyl)phosphonic acid (3 entities in total)
• Functional Keywords: purine salvage, inhibitor, phosphonate, drug lead, transferase-inhibitor complex, transferase/inhibitor
• Biological source: Trypanosoma brucei brucei
• Total number of polymer chains: 6
• Total formula weight: 186205.19

Authors

Guddat, L.W.,Keough, D.T. (deposition date: 2021-09-29, release date: 2022-03-02, Last modification date: 2023-10-18)

Primary citation

Klejch, T.,Keough, D.T.,King, G.,Dolezelova, E.,Cesnek, M.,Budesinsky, M.,Zikova, A.,Janeba, Z.,Guddat, L.W.,Hockova, D.
Stereo-Defined Acyclic Nucleoside Phosphonates are Selective and Potent Inhibitors of Parasite 6-Oxopurine Phosphoribosyltransferases.
J.Med.Chem., 65:4030-4057, 2022

PubMed Abstract: Pathogens such as and spp. are unable to synthesize purine nucleobases. They rely on the salvage of these purines and their nucleosides from the host cell to synthesize the purine nucleotides required for DNA/RNA production. The key enzymes in this pathway are purine phosphoribosyltransferases (PRTs). Here, we synthesized 16 novel acyclic nucleoside phosphonates, 12 with a chiral center at C-2', and eight bearing a second chiral center at C-6'. Of these, bisphosphonate (,)- is the most potent inhibitor of the and 6-oxopurine PRTs and the most potent inhibitor of two () 6-oxopurine PRTs yet discovered, with values as low as 2 nM. Crystal structures of (,)- in complex with human and 6-oxopurine PRTs show that the inhibitor binds to the enzymes in different conformations, providing an explanation for its potency and selectivity (, 35-fold in favor of the parasite enzymes).

PubMed: 35175749
DOI: 10.1021/acs.jmedchem.1c01881

Experimental method

X-RAY DIFFRACTION (2.12068485322 Å)