Potentiating AZT activation: structures of wild-type and mutant human thymidylate kinase suggest reasons for the mutants’ improved kinetics with the HIV prodrug metabolite AZTMP11Edited by J. Karn

Autor: Ostermann, Nils, Lavie, Arnon, Padiyar, Sreekanta, Brundiers, Ralf, Veit, Thomas, Reinstein, Jochen, Goody, Roger S, Konrad, Manfred, Schlichting, Ilme
Zdroj: JMB Online (Journal of Molecular Biology); November 2000, Vol. 304 Issue: 1 p43-53, 11p
Abstrakt: 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 colienzyme 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.
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