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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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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: http://hdl.handle.net/11858/00-001M-0000-002C-215D-E
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.