4IJQ
Human hypoxanthine-guanine phosphoribosyltransferase in complex with [(2-((Guanine-9H-yl)methyl)propane-1,3-diyl)bis(oxy)]bis(methylene))diphosphonic acid
Summary for 4IJQ
| Entry DOI | 10.2210/pdb4ijq/pdb |
| Related | 1BZY 1CJB 1HMP 3GEP |
| Descriptor | Hypoxanthine-guanine phosphoribosyltransferase, [{2-[(guanine-9-yl)methyl]propane-1,3-diyl}bis(oxymethylene)]bis(phosphonic acid), SULFATE ION, ... (5 entities in total) |
| Functional Keywords | gmp, transferase |
| Biological source | Homo sapiens (human) |
| Cellular location | Cytoplasm: P00492 |
| Total number of polymer chains | 4 |
| Total formula weight | 103528.08 |
| Authors | Guddat, L.W.,Keough, D.T.,Hockova, D. (deposition date: 2012-12-22, release date: 2013-03-27, Last modification date: 2024-03-20) |
| Primary citation | Keough, D.T.,Spacek, P.,Hockova, D.,Tichy, T.,Vrbkova, S.,Slavetinska, L.,Janeba, Z.,Naesens, L.,Edstein, M.D.,Chavchich, M.,Wang, T.H.,Jersey, J.,Guddat, L.W. Acyclic nucleoside phosphonates containing a second phosphonate group are potent inhibitors of 6-oxopurine phosphoribosyltransferases and have antimalarial activity J.Med.Chem., 56:2513-2526, 2013 Cited by PubMed Abstract: Acyclic nucleoside phosphonates (ANPs) that contain a 6-oxopurine base are good inhibitors of the Plasmodium falciparum (Pf) and Plasmodium vivax (Pv) 6-oxopurine phosphoribosyltransferases (PRTs). Chemical modifications based on the crystal structure of 2-(phosphonoethoxy)ethylguanine (PEEG) in complex with human HGPRT have led to the design of new ANPs. These novel compounds contain a second phosphonate group attached to the ANP scaffold. {[(2-[(Guanine-9H-yl)methyl]propane-1,3-diyl)bis(oxy)]bis(methylene)}diphosphonic acid (compound 17) exhibited a Ki value of 30 nM for human HGPRT and 70 nM for Pf HGXPRT. The crystal structure of this compound in complex with human HGPRT shows that it fills or partially fills three critical locations in the active site: the binding sites of the purine base, the 5'-phosphate group, and pyrophosphate. This is the first HG(X)PRT inhibitor that has been able to achieve this result. Prodrugs have been synthesized resulting in IC50 values as low as 3.8 μM for Pf grown in cell culture, up to 25-fold lower compared to the parent compounds. PubMed: 23448281DOI: 10.1021/jm301893b PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.004 Å) |
Structure validation
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