Identification of a non-competitive inhibitor of Plasmodium falciparum aspartate transcarbamoylaseLunev, S., Bosch, S. S., Batista, F. A., Wang, C., Li, J., Linzke, M., Kruithof, P., Chamoun, G., Dömling, A. S. S., Wrenger, C. & Groves, M. R., 11-Mar-2018, In : Biochemical and Biophysical Research Communications. 497, 3, p. 835-842 8 p.
Research output: Contribution to journal › Article › Academic › peer-review
Aspartate transcarbamoylase catalyzes the second step of de-novo pyrimidine biosynthesis. As malarial parasites lack pyrimidine salvage machinery and rely on de-novo production for growth and proliferation, this pathway is a target for drug discovery. Previously, an apo crystal structure of aspartate transcarbamoylase from Plasmodium falciparum (PfATC) in its T-state has been reported. Here we present crystal structures of PfATC in the liganded R-state as well as in complex with the novel inhibitor, 2,3-napthalenediol, identified by high-throughput screening. Our data shows that 2,3-napthalediol binds in close proximity to the active site, implying an allosteric mechanism of inhibition. Furthermore, we report biophysical characterization of 2,3-napthalenediol. These data provide a promising starting point for structure based drug design targeting PfATC and malarial de-novo pyrimidine biosynthesis.
|Number of pages||8|
|Journal||Biochemical and Biophysical Research Communications|
|Early online date||21-Feb-2018|
|Publication status||Published - 11-Mar-2018|
- Journal Article