1E9A

Human thymidylate kinase complexed with the bisubstrate inhibitor AZTP5A

Summary for 1E9A

• Entry DOI: 10.2210/pdb1e9a/pdb
• Related: 1E2D 1E2E 1E2F 1E2G 1E2Q 1E98 1E99 1E9B 1E9C 1E9D 1E9E 1E9F
• Descriptor: THYMIDYLATE KINASE, P1-(5'-ADENOSYL)P5-(5'-(3'AZIDO-3'-DEOXYTHYMIDYL))PENTAPHOSPHATE, MAGNESIUM ION, ... (4 entities in total)
• Functional Keywords: phosphotransferase, thymidylate kinase, p-loop, transferase
• Biological source: HOMO SAPIENS (HUMAN)
• Total number of polymer chains: 1
• Total formula weight: 25012.47

Authors

Ostermann, N.,Lavie, A.,Padiyar, S.,Brundiers, R.,Veit, T.,Reintein, J.,Goody, R.S.,Konrad, M.,Schlichting, I. (deposition date: 2000-10-10, release date: 2001-10-05, Last modification date: 2024-05-08)

Primary citation

Ostermann, N.,Lavie, A.,Padiyar, S.,Brundiers, R.,Veit, T.,Reintein, J.,Goody, R.S.,Konrad, M.,Schlichting, I.
Potentiating Azt Activation: Structures of Wildtype and Mutant Human Thymidylate Kinase Suggest Reasons for the Mutants' Improved Kinetics with the HIV Prodrug Metabolite Aztmp
J.Mol.Biol., 304:43-, 2000

PubMed 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.

PubMed: 11071809
DOI: 10.1006/JMBI.2000.4175

Experimental method

X-RAY DIFFRACTION (1.6 Å)