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  Structures of human thymidylate kinase in complex with prodrugs: Implications for the structure-based design of novel compounds

Ostermann, N., Segura-Pena, D., Meier, C., Veit, T., Monnerjahn, C., Konrad, M., et al. (2003). Structures of human thymidylate kinase in complex with prodrugs: Implications for the structure-based design of novel compounds. Biochemistry, 42(9), 2568-2577. Retrieved from http://pubs.acs.org/doi/pdfplus/10.1021/bi027302t.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0010-941E-E Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0027-F118-9
Genre: Journal Article

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Ostermann, N., Author
Segura-Pena, D., Author
Meier, C., Author
Veit, T., Author
Monnerjahn, C.1, Author              
Konrad, M.2, Author              
Lavie, A., Author
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1Department of Molecular Genetics, MPI for biophysical chemistry, Max Planck Society, ou_578622              
2Research Group of Enzyme Biochemistry, MPI for biophysical chemistry, Max Planck Society, ou_578612              

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 Abstract: Nucleoside analogue prodrugs are dependent on efficient intracellular stepwise phosphorylation to their triphosphate form to become therapeutically active. In many cases it is this activation pathway that largely determines the efficacy of the drug. To gain further understanding of the determinants for efficient conversion by the enzyme thymidylate kinase (TMPK) of clinically important thymidine monophosphate analogues to the corresponding diphosphates, we solved the crystal structures of the enzyme, with either ADP or the ATP analogue AppNHp at the phosphoryl donor site, in complex with TMP, AZTMP (previous work), NH2TMP, d4TMP, ddTMP, and FLTMP (this work) at the phosphoryl acceptor site. In conjunction with steady-state kinetic data, our structures shed light on the effect of 3'- substitutions in the nucleoside monophosphate (NMP) sugar moiety on the catalytic rate. We observe a direct correlation between the rate of phosphorylation of an NMP and its ability to induce a closing of the enzyme's phosphate-binding loop (P- loop). Our results show the drastic effects that slight modifications of the substrates exert on the enzyme's conformation and, hence, activity and suggest the type of substitutions that are compatible with efficient phosphorylation by TMPK.

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Language(s): eng - English
 Dates: 2003-03-11
 Publication Status: Published in print
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 Rev. Method: Peer
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Title: Biochemistry
Source Genre: Journal
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Pages: - Volume / Issue: 42 (9) Sequence Number: - Start / End Page: 2568 - 2577 Identifier: -