Identification of a non-competitive inhibitor of Plasmodium falciparum aspartate transcarbamoylase

Sergey Lunev, Soraya S Bosch, Fernando A Batista, Chao Wang, Jingyao Li, Marleen Linzke, Paul Kruithof, George Chamoun, Alexander S S Dömling, Carsten Wrenger, Matthew R Groves

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Abstract

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.

Original languageEnglish
Pages (from-to)835-842
Number of pages8
JournalBiochemical and Biophysical Research Communications
Volume497
Issue number3
Early online date21-Feb-2018
DOIs
Publication statusPublished - 11-Mar-2018

Keywords

  • Journal Article

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