6FBA

Crystal Structure of truncated aspartate transcarbamoylase from Plasmodium falciparum with bound inhibitor 2,3-naphthalenediol

Summary for 6FBA

• Entry DOI: 10.2210/pdb6fba/pdb
• Related: 5ILQ
• Descriptor: Aspartate transcarbamoylase, SULFATE ION, naphthalene-2,3-diol, ... (10 entities in total)
• Functional Keywords: falciparum malaria pyrimidine biosynthesis trimer hit inhibitor, transferase
• Biological source: Plasmodium falciparum (malaria parasite P. falciparum); More
• Total number of polymer chains: 3
• Total formula weight: 122700.87

Authors

Lunev, S.,Bosch, S.S.,Batista, F.A.,Wang, C.,Wrenger, C.,Groves, M.R. (deposition date: 2017-12-18, release date: 2018-02-21, Last modification date: 2024-10-16)

Primary citation

Lunev, S.,Bosch, S.S.,Batista, F.A.,Wang, C.,Li, J.,Linzke, M.,Kruithof, P.,Chamoun, G.,Domling, A.S.S.,Wrenger, C.,Groves, M.R.
Identification of a non-competitive inhibitor of Plasmodium falciparum aspartate transcarbamoylase.
Biochem. Biophys. Res. Commun., 497:835-842, 2018

PubMed 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.

PubMed: 29476738
DOI: 10.1016/j.bbrc.2018.02.112

Experimental method

X-RAY DIFFRACTION (2 Å)