期刊
PLOS NEGLECTED TROPICAL DISEASES
卷 5, 期 5, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pntd.0001164
关键词
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资金
- Swiss National Science Foundation [3100A0-120566/1]
- European Union (Prokinase Network) [503467]
Background: The essential purine salvage pathway of Trypanosoma brucei bears interesting catalytic enzymes for chemotherapeutic intervention of Human African Trypanosomiasis. Unlike mammalian cells, trypanosomes lack de novo purine synthesis and completely rely on salvage from their hosts. One of the key enzymes is adenosine kinase which catalyzes the phosphorylation of ingested adenosine to form adenosine monophosphate (AMP) utilizing adenosine triphosphate (ATP) as the preferred phosphoryl donor. Methods and Findings: Here, we present the first structures of Trypanosoma brucei rhodesiense adenosine kinase (TbrAK): lthe structure of TbrAK in complex with the bisubstrate inhibitor P-1,P-5-di(adenosine-5')-pentaphosphate (AP5A) at 1.55 angstrom, and TbrAK complexed with the recently discovered activator 4-[5-(4-phenoxyphenyl)-2H-pyrazol-3-yl]morpholine (compound 1) at 2.8 angstrom resolution. Conclusions: The structural details and their comparison give new insights into substrate and activator binding to TbrAK at the molecular level. Further structure-activity relationship analyses of a series of derivatives of compound 1 support the observed binding mode of the activator and provide a possible mechanism of action with respect to their activating effect towards TbrAK.
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