1e9c
MUTANT HUMAN THYMIDYLATE KINASE COMPLEXED WITH TMP AND APPNP
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OverviewOverview
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.
About this StructureAbout this Structure
1E9C is a Single protein structure of sequence from Homo sapiens with MG, TMP and ADP as ligands. Active as dTMP kinase, with EC number 2.7.4.9 Structure known Active Site: TMP. Full crystallographic information is available from OCA.
ReferenceReference
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., Ostermann N, Lavie A, Padiyar S, Brundiers R, Veit T, Reinstein J, Goody RS, Konrad M, Schlichting I, J Mol Biol. 2000 Nov 17;304(1):43-53. PMID:11071809
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