Student Posters 51st Lorne Proteins Conference 2026

Characterisation and drug discovery targeting PfSET7, a motility-associated lysine methyltransferase in Plasmodium falciparum (#141)

George Kobakhidze 1 2 , Yulia Pivovarova 1 , Berta Ladinig 1 3 , Ivona Josipovic 1 4 , Vanessa Pichler 1 3 , Hannah Rohrmoser 1 5 , Liwang Cui 6 7 , Jun Miao 6 7 , Gang Dong 1
  1. Max Perutz Labs, Medical University of Vienna, Vienna, Austria
  2. Vienna Biocenter PhD Program, a Doctoral School of the University of Vienna and the Medical University of Vienna, Vienna, Austria
  3. University of Vienna, Vienna, Austria
  4. University of Applied Sciences Technikum Vienna, Vienna, Austria
  5. Hochschule Campus Wien, Vienna, Austria
  6. Department of Internal Medicine, University of South Florida, Tampa, Florida, USA
  7. Center for Global Health and Infectious Diseases Research, College of Public Health, University of South Florida, Tampa, Florida, USA

Apicomplexan parasites such as Plasmodium falciparum and Toxoplasma gondii cause malaria and toxoplasmosis, respectively, which afflict millions worldwide. In T. gondii, a lysine (K) methyltransferase (KMT) localises to the apical complex in tachyzoites and regulates parasite egress. This enzyme, termed apical complex KMT (TgAKMT), is an SET-domain-containing KMT with orthologues in other apicomplexan species, including PfSET7 in P. falciparum. Both enzymes localise to the parasite’s apical complex and play key roles in regulating motility. Owing to their distinct structural features and essential cellular roles, AKMTs represent promising targets for anti-parasitic drug development.

PfSET7 was crystallised, and its structure was determined to ~2.1 Å resolution. It adopts a tertiary fold highly similar to TgAKMT and forms homodimers in a concentration-dependent manner. Uniquely, PfSET7 contains a beta-hairpin within the SET domain, which is conserved only in orthologues belonging to the Hematozoa subclass, such as Babesia and Theileria spp. Deletion of the hairpin drastically reduces enzymatic activity, whereas substitution with the homologous beta-hairpin from Theileria parvum preserves function. PfSET7 also contains four conserved motifs within its intrinsically disordered N-terminal region, found exclusively in Plasmodium spp., which may enable liquid-liquid phase separation, as suggested by our preliminary studies. The cellular functions of both of these distinct PfSET7 features remain to be elucidated.

All AKMT orthologues share a conserved, unique pocket adjacent to the substrate lysine channel, presenting an attractive site for inhibitor binding. A high-throughput screen of ~70,000 compounds identified six hits that specifically inhibit PfSET7 activity. These initial hits are currently being optimised to generate more potent and selective inhibitors.

Together, our studies will deepen understanding of this unique KMT family and apicomplexan biology. In parallel, the drug discovery aspect of this work holds promise for delivering novel therapeutic strategies against malaria, toxoplasmosis, and related diseases.

  1. Pivovarova Y, Liu J, Lesigang J, Koldyka O, Rauschmeier R, Hu K, Dong G. Structure of a Novel Dimeric SET Domain Methyltransferase that Regulates Cell Motility. J Mol Biol. 2018 Oct 19;430(21):4209-4229. doi: 10.1016/j.jmb.2018.08.017. Epub 2018 Aug 24. PMID: 30148980; PMCID: PMC7141177.
  2. Chen, P., Ding, S., Zanghì, G. et al. Plasmodium falciparum PfSET7: enzymatic characterization and cellular localization of a novel protein methyltransferase in sporozoite, liver and erythrocytic stage parasites. Sci Rep 6, 21802 (2016). https://doi.org/10.1038/srep21802