6bo7 | pdb_00006bo7

Crystal structure of Plasmodium vivax hypoxanthine guanine phosphoribosyltransferase in complex with [3R,4R]-4-guanin-9-yl-3-((S)-2-hydroxy-2-phosphonoethyl)oxy-1-N-(phosphonopropionyl)pyrrolidine

spinqualitylabelsall models 6bo7, resolution 2.86Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6bo7 is a 12 chain structure with sequence from Haemamoeba vivax. This structure supersedes the now removed PDB entry 5hhu. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: MG, YPG Gene: PVC01_080017300, PVP01_0812500, PVT01_080017400 (Haemamoeba vivax) Activity: Hypoxanthine phosphoribosyltransferase, with EC number 2.4.2.8 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed Plasmodium falciparum (Pf) and Plasmodium vivax (Pv) are the foremost causative agents of malaria. Due to the development of resistance to current antimalarial medications, new drugs for this parasitic disease need to be discovered. The activity of hypoxanthine-guanine-[xanthine]-phosphoribosyltransferase, HG[X]PRT, is reported to be essential for the growth of both of these parasites, making it an excellent target for antimalarial drug discovery. Here, we have used rational structure-based methods to design an inhibitor, [3R,4R]-4-guanin-9-yl-3-((S)-2-hydroxy-2-phosphonoethyl)oxy-1-N-(phosphonopropion yl)pyrrolidine, of PvHGPRT and PfHGXPRT that has Ki values of 8 and 7 nM, respectively, for these two enzymes. The crystal structure of PvHGPRT in complex with this compound has been determined to 2.85 A resolution. The corresponding complex with human HGPRT was also obtained to allow a direct comparison of the binding modes of this compound with the two enzymes. The tetra-(ethyl l-phenylalanine) tetraamide prodrug of this compound was synthesized, and it has an IC50 of 11.7 +/- 3.2 muM against Pf lines grown in culture and a CC50 in human A549 cell lines of 102 +/- 11 muM, thus giving it a approximately 10-fold selectivity index. Design of Plasmodium vivax Hypoxanthine-Guanine Phosphoribosyltransferase Inhibitors as Potential Antimalarial Therapeutics.,Keough DT, Rejman D, Pohl R, Zbornikova E, Hockova D, Croll T, Edstein MD, Birrell GW, Chavchich M, Naesens LMJ, Pierens GK, Brereton IM, Guddat LW ACS Chem Biol. 2017 Dec 5. doi: 10.1021/acschembio.7b00916. PMID:29161011 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Phosphoribosyltransferase 3D structures

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