7SAN
Crystal structure of human hypoxanthine guanine phosphoribzosyltransferase in complex with (4S,7S)-7-hydroxy-4-((guanin-9-yl)methyl)-2,5-dioxaheptan-1,7-diphosphonate
Summary for 7SAN
| Entry DOI | 10.2210/pdb7san/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 | inhibitor, complex, phosphonate, purine, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 4 |
| Total formula weight | 99313.06 |
| Authors | Guddat, L.W.,Keough, D.T. (deposition date: 2021-09-22, release date: 2022-05-18, 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 Cited by 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: 35175749DOI: 10.1021/acs.jmedchem.1c01881 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.58155523622 Å) |
Structure validation
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