8TS4
Crystal structure of T. Brucei hypoxanthine guanine phosphoribosyltransferase in complex with [2S,4S]-4-Guanin-9-yl-2-(2-phosphonoethoxymethyl)-1-N-(3-phosphonopropionyl)pyrrolidine
Summary for 8TS4
| Entry DOI | 10.2210/pdb8ts4/pdb |
| Descriptor | Hypoxanthine-guanine phosphoribosyltransferase, MAGNESIUM ION, (3-{(2S,4S)-4-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)-2-[(2-phosphonoethoxy)methyl]pyrrolidin-1-yl}-3-oxopropyl)phosphonic acid, ... (4 entities in total) |
| Functional Keywords | inhibitor, complex, purine base, product analog, transferase |
| Biological source | Trypanosoma brucei |
| Total number of polymer chains | 2 |
| Total formula weight | 47823.06 |
| Authors | Guddat, L.W.,Guddat, L.W. (deposition date: 2023-08-10, release date: 2024-05-08, Last modification date: 2024-05-22) |
| Primary citation | Keough, D.T.,Petrova, M.,King, G.,Kratochvil, M.,Pohl, R.,Dolezelova, E.,Zikova, A.,Guddat, L.W.,Rejman, D. Development of Prolinol Containing Inhibitors of Hypoxanthine-Guanine-Xanthine Phosphoribosyltransferase: Rational Structure-Based Drug Design. J.Med.Chem., 67:7158-7175, 2024 Cited by PubMed Abstract: Inhibition of hypoxanthine-guanine-xanthine phosphoribosyltransferase activity decreases the pool of 6-oxo and 6-amino purine nucleoside monophosphates required for DNA and RNA synthesis, resulting in a reduction in cell growth. Therefore, inhibitors of this enzyme have potential to control infections, caused by and , , , and . Five compounds synthesized here that contain a purine base covalently linked by a prolinol group to one or two phosphonate groups have values ranging from 3 nM to >10 μM, depending on the structure of the inhibitor and the biological origin of the enzyme. X-ray crystal structures show that, on binding, these prolinol-containing inhibitors stimulated the movement of active site loops in the enzyme. Against in cell culture, a prodrug exhibited an EC of 10 μM. Thus, these compounds are excellent candidates for further development as drug leads against infectious diseases as well as being potential anticancer agents. PubMed: 38651522DOI: 10.1021/acs.jmedchem.4c00021 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.2 Å) |
Structure validation
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