biostudies-literatureLe Berre MNational Institute of Allergy and Infectious DiseasesVetenskapsrådetFrench Infrastructure for Integrated Structural BiologyNIAID NIH HHSUniversité Paris-Saclay, Ecoles doctorales, Université Paris-SaclayCNRS ATIP-AvenirGrand Équipement National De Calcul IntensifANRS-MIEMinistère de l'Education Nationale, de l'Enseignement Superieur et de la Recherche38-48https://www.ebi.ac.uk/biostudies/studies/S-EPMC11740583biostudies-literatureUnknown81(Pt 1)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 hydrActa crystallographica. Section D, Structural biologyStructural characterization of the ACDC domain from ApiAP2 proteins, a potential molecular target against apicomplexan parasites.PMC11740583ECTZ189696R01AI125565AD010714400ANR-10-INSB-05-05R01 AI125565Lazar NLi de la Sierra-Gallay ITubiana TLlinas MReutersward Waldner PSantos JMLe Berre MNessler SfalseStructural 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 hydr2025-01-01T00:00:00Z2025 Jan2026-07-15T13:51:54.585Z2026-07-05T03:11:30.655ZS-EPMC117405833982002710.1107/S205979832401251810.1107/s2059798324012518