Structural Characterization of the ACDC Domain from ApiAP2 Proteins, a Potential Molecular Target Against Apicomplexan Parasites

Overview

Journal Acta Crystallogr D Struct Biol

Date 2025 Jan 17

PMID 39820027

Authors

Marine Le Berre

Thibault Tubiana

Philippa Reutersward Waldner

Noureddine Lazar

Ines Li de la Sierra-Gallay

Joana M Santos

Manuel Llinas

Sylvie Nessler

Affiliations

Soon will be listed here.

Abstract

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.

References

Krissinel E, Henrick K . Secondary-structure matching (SSM), a new tool for fast protein structure alignment in three dimensions. Acta Crystallogr D Biol Crystallogr. 2004; 60(Pt 12 Pt 1):2256-68. DOI: 10.1107/S0907444904026460. View

Oehring S, Woodcroft B, Moes S, Wetzel J, Dietz O, Pulfer A . Organellar proteomics reveals hundreds of novel nuclear proteins in the malaria parasite Plasmodium falciparum. Genome Biol. 2012; 13(11):R108. PMC: 4053738. DOI: 10.1186/gb-2012-13-11-r108. View

Yuda M, Kaneko I, Murata Y, Iwanaga S, Nishi T . Mechanisms of triggering malaria gametocytogenesis by AP2-G. Parasitol Int. 2021; 84:102403. DOI: 10.1016/j.parint.2021.102403. View

Nishi T, Kaneko I, Iwanaga S, Yuda M . PbAP2-FG2 and PbAP2R-2 function together as a transcriptional repressor complex essential for Plasmodium female development. PLoS Pathog. 2023; 19(2):e1010890. PMC: 9956629. DOI: 10.1371/journal.ppat.1010890. View

Gouet P, Courcelle E, Stuart D, Metoz F . ESPript: analysis of multiple sequence alignments in PostScript. Bioinformatics. 1999; 15(4):305-8. DOI: 10.1093/bioinformatics/15.4.305. View

Zhang C, Li Z, Cui H, Jiang Y, Yang Z, Wang X . Systematic CRISPR-Cas9-Mediated Modifications of ApiAP2 Genes Reveal Functional Insights into Parasite Development. mBio. 2017; 8(6). PMC: 5727417. DOI: 10.1128/mBio.01986-17. View

Emsley P, Lohkamp B, Scott W, Cowtan K . Features and development of Coot. Acta Crystallogr D Biol Crystallogr. 2010; 66(Pt 4):486-501. PMC: 2852313. DOI: 10.1107/S0907444910007493. View

Mazanetz M, Marmon R, Reisser C, Morao I . Drug discovery applications for KNIME: an open source data mining platform. Curr Top Med Chem. 2012; 12(18):1965-79. DOI: 10.2174/156802612804910331. View

McCoy A, Grosse-Kunstleve R, Adams P, Winn M, Storoni L, Read R . Phaser crystallographic software. J Appl Crystallogr. 2009; 40(Pt 4):658-674. PMC: 2483472. DOI: 10.1107/S0021889807021206. View

10.

Lin Z, Akin H, Rao R, Hie B, Zhu Z, Lu W . Evolutionary-scale prediction of atomic-level protein structure with a language model. Science. 2023; 379(6637):1123-1130. DOI: 10.1126/science.ade2574. View

11.

Painter H, Campbell T, Llinas M . The Apicomplexan AP2 family: integral factors regulating Plasmodium development. Mol Biochem Parasitol. 2010; 176(1):1-7. PMC: 3026892. DOI: 10.1016/j.molbiopara.2010.11.014. View

12.

Wang J, Wolf R, Caldwell J, Kollman P, Case D . Development and testing of a general amber force field. J Comput Chem. 2004; 25(9):1157-74. DOI: 10.1002/jcc.20035. View

13.

Tenter A, Heckeroth A, Weiss L . Toxoplasma gondii: from animals to humans. Int J Parasitol. 2000; 30(12-13):1217-58. PMC: 3109627. DOI: 10.1016/s0020-7519(00)00124-7. View

14.

Alsaady I . and irritable bowel syndrome. Trop Parasitol. 2024; 14(1):8-15. PMC: 10911187. DOI: 10.4103/tp.tp_10_23. View

15.

Tebben K, Bradwell K, Serre D . Variation in selective constraints along the Plasmodium life cycle. Infect Genet Evol. 2021; 92:104908. PMC: 8205998. DOI: 10.1016/j.meegid.2021.104908. View

16.

Santos J, Josling G, Ross P, Joshi P, Orchard L, Campbell T . Red Blood Cell Invasion by the Malaria Parasite Is Coordinated by the PfAP2-I Transcription Factor. Cell Host Microbe. 2017; 21(6):731-741.e10. PMC: 5855115. DOI: 10.1016/j.chom.2017.05.006. View

17.

Mirdita M, Schutze K, Moriwaki Y, Heo L, Ovchinnikov S, Steinegger M . ColabFold: making protein folding accessible to all. Nat Methods. 2022; 19(6):679-682. PMC: 9184281. DOI: 10.1038/s41592-022-01488-1. View

18.

Quiroga R, Villarreal M . Vinardo: A Scoring Function Based on Autodock Vina Improves Scoring, Docking, and Virtual Screening. PLoS One. 2016; 11(5):e0155183. PMC: 4865195. DOI: 10.1371/journal.pone.0155183. View

19.

Morris G, Huey R, Lindstrom W, Sanner M, Belew R, Goodsell D . AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J Comput Chem. 2009; 30(16):2785-91. PMC: 2760638. DOI: 10.1002/jcc.21256. View

20.

Gamo F, Sanz L, Vidal J, de Cozar C, Alvarez E, Lavandera J . Thousands of chemical starting points for antimalarial lead identification. Nature. 2010; 465(7296):305-10. DOI: 10.1038/nature09107. View