8tpv

Structure of human hypoxanthine guanine phosphoribzosyltransferase in complex with [2S,4R]-4-Guanin-9-yl-2-(2-phosphonoethoxymethyl)-1-N-(3-phosphonopropionyl)pyrrolidine

spinqualitylabelsall models 8tpv, resolution 2.27Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8tpv is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.27Å Ligands: JEI, MG Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease HPRT_HUMAN Defects in HPRT1 are the cause of Lesch-Nyhan syndrome (LNS) [MIM:300322. LNS is characterized by complete lack of enzymatic activity that results in hyperuricemia, choreoathetosis, mental retardation, and compulsive self-mutilation. Defects in HPRT1 are the cause of gout HPRT-related (GOUT-HPRT) [MIM:300323; also known as HPRT-related gout or Kelley-Seegmiller syndrome. Gout is characterized by partial enzyme activity and hyperuricemia. [:] Function HPRT_HUMAN 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. 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.

Proteopedia Page Contributors and Editors (what is this?)

OCA