7ZEA

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

Summary for 7ZEA

• Entry DOI: 10.2210/pdb7zea/pdb
• Descriptor: Aspartate carbamoyltransferase, O-benzylhydroxylamine, SULFATE ION, ... (5 entities in total)
• Functional Keywords: aspartate transcarbamoylase, plasmodium falciparum, fragment-based screening, inhibitor., transferase
• Biological source: Plasmodium falciparum 3D7
• Total number of polymer chains: 3
• Total formula weight: 121513.71

Authors

Wang, C.,Zhang, B. (deposition date: 2022-03-30, release date: 2022-08-24, Last modification date: 2024-01-31)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.448 Å)