1e9a

From Proteopedia

Revision as of 09:45, 30 October 2007

HUMAN THYMIDYLATE KINASE COMPLEXED WITH THE BISUBSTRATE INHIBITOR AZTP5A

Overview

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 Structure

1E9A is a [Single protein] structure of sequence from [Homo sapiens] with MG and Z5A as [ligands]. Active as [dTMP kinase], with EC number [2.7.4.9]. Structure known Active Site: Z5A. Full crystallographic information is available from [OCA].

Reference

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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