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Journal Article

Potentiating AZT activation: structures of wild-type and mutant human thymidylate kinase suggest reasons for the mutants' improved kinetics with the HIV prodrug metabolite AZTMP

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Reinstein,  Jochen
Department of Biomolecular Mechanisms, Max Planck Institute for Medical Research, Max Planck Society;

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Schlichting,  Ilme
Department of Biomolecular Mechanisms, Max Planck Institute for Medical Research, Max Planck Society;

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https://www.sciencedirect.com/science/article/pii/S0022283600941755/pdfft?md5=b7917969be673aabf9b643da08031fe8&pid=1-s2.0-S0022283600941755-main.pdf
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https://doi.org/10.1006/jmbi.2000.4175
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Citation

Ostermann, N., Lavie, A., Padiyar, S., Brundiers, R., Veit, T., Reinstein, J., et al. (2000). Potentiating AZT activation: structures of wild-type and mutant human thymidylate kinase suggest reasons for the mutants' improved kinetics with the HIV prodrug metabolite AZTMP. Journal of Molecular Biology (London), 304(1), 43-53. doi:10.1006/jmbi.2000.4175.


Cite as: https://hdl.handle.net/21.11116/0000-0002-44E4-0
Abstract
The 60-fold reduced phosphorylation rate of azidothymidine (AZT) monophosphate (AZTMP), the partially activated AZT metabolite, by human thymidylate kinase (TMPK) severely limits the efficacy of this anti-HIV prodrug. Crystal structures of different TMPK nucleotide complexes indicate that steric hindrance by the azido group of AZTMP prevents formation of the catalytically active closed conformation of the P-loop of TMPK. The F105Y mutant and a chimeric mutant that contains sequences of the human and Escherichia coli enzyme phosphorylate AZTMP 20-fold faster than the wild-type enzyme. The structural basis of the increased activity is assigned to stabilization of the closed P-loop conformation.