7ZEA

Crystal Structure of truncated aspartate transcarbamoylase from Plasmodium falciparum with bound inhibitor O-benzylhydroxylamine

7ZEA の概要

• エントリーDOI: 10.2210/pdb7zea/pdb
• 分子名称: Aspartate carbamoyltransferase, O-benzylhydroxylamine, SULFATE ION, ... (5 entities in total)
• 機能のキーワード: aspartate transcarbamoylase, plasmodium falciparum, fragment-based screening, inhibitor., transferase
• 由来する生物種: Plasmodium falciparum 3D7
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 121513.71

構造登録者

Wang, C.,Zhang, B. (登録日: 2022-03-30, 公開日: 2022-08-24, 最終更新日: 2024-01-31)

主引用文献

Wang, C.,Zhang, B.,Kruger, A.,Du, X.,Visser, L.,Domling, A.S.S.,Wrenger, C.,Groves, M.R.
Discovery of Small-Molecule Allosteric Inhibitors of Pf ATC as Antimalarials.
J.Am.Chem.Soc., 144:19070-19077, 2022

PubMed Abstract: The discovery and development of new drugs against malaria remain urgent. Aspartate transcarbamoylase (ATC) has been suggested to be a promising target for antimalarial drug development. Here, we describe a series of small-molecule inhibitors of ATC with low nanomolar binding affinities that selectively bind to a previously unreported allosteric pocket, thereby inhibiting ATC activation. We demonstrate that the buried allosteric pocket is located close to the traditional ATC active site and that reported compounds maintain the active site of ATC in its low substrate affinity/low activity conformation. These compounds inhibit parasite growth in blood stage cultures at single digit micromolar concentrations, whereas limited effects were seen against human normal lymphocytes. To our knowledge, this series represent the first ATC-specific allosteric inhibitors.

PubMed: 36195578
DOI: 10.1021/jacs.2c08128

実験手法

X-RAY DIFFRACTION (2.448 Å)