Structural characterization of the ACDC domain from ApiAP2 proteins, a potential molecular target against apicomplexan parasites
The apicomplexan AP2 (ApiAP2) proteins are the best characterized family of DNA-binding proteins in Plasmodium spp. malaria parasites. Apart from the AP2 DNA-binding domain, there is little sequence similarity between ApiAP2 proteins. However, a conserved AP2-coincident domain mostly at the C-terminus (ACDC domain) is observed in a subset of the ApiAP2 proteins. The structure and function of this domain remain unknown. We report two crystal structures of ACDC domains derived from distinct Plasmodium ApiAP2 proteins, revealing a conserved, unique, noncanonical, four-helix bundle architecture. We used these structures to perform in silico docking calculations against a library of known antimalarial compounds and identified potential small-molecule ligands that bind in a highly conserved hydrophobic pocket that is present in all apicomplexan ACDC domains. These ligands provide a new molecular basis for the future design of ACDC inhibitors.
Authors
- Manuel Llinás (ORCID: https://orcid.org/0000-0002-6173-5882)
- Joana Santos (ORCID: https://orcid.org/0000-0002-5411-4439)
- Philippa Reuterswärd
- Thibault Tubiana (ORCID: https://orcid.org/0000-0002-6490-4602)
- Sylvie Nessler (ORCID: https://orcid.org/0000-0003-4973-9941)
- I. Li de la Sierra-Gallay (ORCID: https://orcid.org/0000-0003-2770-7439)
- Noureddine Lazar
- Marine Le Berre
Institutions
- Centre National de la Recherche Scientifique (FR)
- Pennsylvania State University (US)
- Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR)
- Université Paris-Saclay (FR)
- Institut de Biologie Intégrative de la Cellule (FR)
- CEA Paris-Saclay (FR)
Publication Details
- Journal
- Acta Crystallographica Section D Structural Biology
- Published
- 2024-12-28
- DOI
- https://doi.org/10.1107/s2059798324012518
- Citations
- 2
- Primary Topic
- Malaria Research and Control
- Type
- article
- Field-Weighted Citation Impact
- 1.09
Funders
- Vetenskapsrådet
- Ministère de l'Education Nationale, de l'Enseignement Superieur et de la Recherche
- Grand Équipement National De Calcul Intensif
- French Infrastructure for Integrated Structural Biology
- Ecoles doctorales, Université Paris-Saclay
- National Institute of Allergy and Infectious Diseases