2xx3

HUMAN THYMIDYLATE KINASE COMPLEXED WITH thymidine butenyl phosphonate monophosphate and ADP

spinqualitylabelsall models 2xx3, resolution 2.00Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 2xx3 is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: ADP, MG, NO3, TAE Related: 1e2d, 1e2g, 1e9a, 1e9b, 1e98, 1nn3, 1e2e, 1e9e, 1e2q, 1e99, 1nmx, 1nn5, 1nmz, 1nn1, 1e9d, 1nmy, 1e2f, 1nn0, 1e9f, 1e9c Activity: dTMP kinase, with EC number 2.7.4.9 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [KTHY_HUMAN] Catalyzes the conversion of dTMP to dTDP. Publication Abstract from PubMed Acyclic nucleoside phosphonates (ANPs) are at the cornerstone of DNA virus and retrovirus therapies. They reach their target, the viral DNA polymerase, after two phosphorylation steps catalyzed by cellular kinases. New pyrimidine ANPs have been synthesized with unsaturated acyclic side chains (prop-2-enyl-, but-2-enyl-, pent-2-enyl-) and different substituents at the C5 position of the uracil nucleobase. Several derivatives in the but-2-enyl- series 9d and 9e, with (E) but not with (Z) configuration, were efficient substrates for human thymidine monophosphate (TMP) kinase, but not for uridine monophosphate-cytosine monophosphate (UMP-CMP) kinase, which is in contrast to cidofovir. Human TMP kinase was successfully crystallized in a complex with phosphorylated (E)-thymidine-but-2-enyl phosphonate 9e and ADP. The bis-pivaloyloxymethyl (POM) esters of (E)-9d and (E)-9e were synthesized and shown to exert activity against herpes virus in vitro (IC(50) = 3 muM) and against varicella zoster virus in vitro (IC(50) = 0.19 muM), in contrast to the corresponding inactive (Z) derivatives. Thus, their antiviral activity correlates with their ability to act as thymidylate kinase substrates. Novel antiviral C5-substituted pyrimidine acyclic nucleoside phosphonates selected as human thymidylate kinase substrates.,Topalis D, Pradere U, Roy V, Caillat C, Azzouzi A, Broggi J, Snoeck R, Andrei G, Lin J, Eriksson S, Alexandre JA, El-Amri C, Deville-Bonne D, Meyer P, Balzarini J, Agrofoglio LA J Med Chem. 2011 Jan 13;54(1):222-32. Epub 2010 Dec 3. PMID:21128666 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Thymidylate kinase

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