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Crystal Structure of truncated aspartate transcarbamoylase from Plasmodium falciparum with bound inhibitor 2,3-naphthalenediolCrystal Structure of truncated aspartate transcarbamoylase from Plasmodium falciparum with bound inhibitor 2,3-naphthalenediol
Structural highlights
FunctionPublication Abstract from PubMedAspartate 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. Identification of a non-competitive inhibitor of Plasmodium falciparum aspartate transcarbamoylase.,Lunev S, Bosch SS, Batista FA, Wang C, Li J, Linzke M, Kruithof P, Chamoun G, Domling ASS, Wrenger C, Groves MR Biochem Biophys Res Commun. 2018 Mar 11;497(3):835-842. doi:, 10.1016/j.bbrc.2018.02.112. Epub 2018 Feb 21. PMID:29476738[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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