6FBA

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

6FBA の概要

• エントリーDOI: 10.2210/pdb6fba/pdb
• 関連するPDBエントリー: 5ILQ
• 分子名称: Aspartate transcarbamoylase, SULFATE ION, naphthalene-2,3-diol, ... (10 entities in total)
• 機能のキーワード: falciparum malaria pyrimidine biosynthesis trimer hit inhibitor, transferase
• 由来する生物種: Plasmodium falciparum (malaria parasite P. falciparum); 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 122700.87

構造登録者

Lunev, S.,Bosch, S.S.,Batista, F.A.,Wang, C.,Wrenger, C.,Groves, M.R. (登録日: 2017-12-18, 公開日: 2018-02-21, 最終更新日: 2024-10-16)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2 Å)