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

spinqualitylabelsall models 8ts4, resolution 2.20Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8ts4 is a 2 chain structure with sequence from Trypanosoma brucei. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.2Å Ligands: KFF, MG Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function HPRT_TRYBB Converts guanine to guanosine monophosphate, and hypoxanthine to inosine monophosphate. Transfers the 5-phosphoribosyl group from 5-phosphoribosylpyrophosphate onto the purine. Plays a central role in the generation of purine nucleotides through the purine salvage pathway (By similarity). Publication Abstract from PubMed 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 Plasmodium falciparum and Plasmodium vivax, Trypanosoma brucei, Mycobacterium tuberculosis, and Helicobacter pylori. Five compounds synthesized here that contain a purine base covalently linked by a prolinol group to one or two phosphonate groups have K(i) values ranging from 3 nM to >10 muM, 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 TBr in cell culture, a prodrug exhibited an EC(50) of 10 muM. Thus, these compounds are excellent candidates for further development as drug leads against infectious diseases as well as being potential anticancer agents. Development of Prolinol Containing Inhibitors of Hypoxanthine-Guanine-Xanthine Phosphoribosyltransferase: Rational Structure-Based Drug Design.,Keough DT, Petrova M, King G, Kratochvil M, Pohl R, Dolezelova E, Zikova A, Guddat LW, Rejman D J Med Chem. 2024 Apr 23. doi: 10.1021/acs.jmedchem.4c00021. PMID:38651522 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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