| Autor: |
Ostermann, N., Lavie, A., Padiyar, S., Brundiers, R., Veit, T., Reinstein, J., Goody, R., Konrad, M., Schlichting, I. |
| Jazyk: |
angličtina |
| Rok vydání: |
2000 |
| Zdroj: |
Journal of Molecular Biology (London) |
| Popis: |
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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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