2XX3

HUMAN THYMIDYLATE KINASE COMPLEXED WITH thymidine butenyl phosphonate monophosphate and ADP

Summary for 2XX3

• Entry DOI: 10.2210/pdb2xx3/pdb
• Related: 1E2D 1E2E 1E2F 1E2G 1E2Q 1E98 1E99 1E9A 1E9B 1E9C 1E9D 1E9E 1E9F 1NMX 1NMY 1NMZ 1NN0 1NN1 1NN3 1NN5
• Descriptor: THYMIDYLATE KINASE, ADENOSINE-5'-DIPHOSPHATE, MAGNESIUM ION, ... (6 entities in total)
• Functional Keywords: transferase, acyclic nucleoside phosphonate
• Biological source: HOMO SAPIENS (HUMAN)
• Total number of polymer chains: 1
• Total formula weight: 26881.42

Authors

Caillat, C.,Meyer, P. (deposition date: 2010-11-08, release date: 2011-12-07, Last modification date: 2024-05-08)

Primary citation

Topalis, D.,Pradere, U.,Roy, V.,Caillat, C.,Azzouzi, A.,Broggi, J.,Snoeck, R.,Andrei, G.,Lin, J.,Eriksson, S.,Alexandre, J.A.C.,El-Amri, C.,Deville-Bonne, D.,Meyer, P.,Balzarini, J.,Agrofoglio, L.A.
Novel Antiviral C5-Substituted Pyrimidine Acyclic Nucleoside Phosphonates Selected as Human Thymidylate Kinase Substrates.
J.Med.Chem., 54:222-, 2011

PubMed Abstract: 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 μM) and against varicella zoster virus in vitro (IC(50) = 0.19 μM), in contrast to the corresponding inactive (Z) derivatives. Thus, their antiviral activity correlates with their ability to act as thymidylate kinase substrates.

PubMed: 21128666
DOI: 10.1021/JM1011462

Experimental method

X-RAY DIFFRACTION (2 Å)