The protein kinase CK2 catalytic domain from Plasmodium falciparum: crystal structure, tyrosine kinase activity and inhibition.
David Ruiz-CarrilloJianqing LinAbbas El SahiliMeng WeiSiu Kwan SzePeter C F CheungChristian DoerigJulien LescarPublished in: Scientific reports (2018)
Malaria causes every year over half-a-million deaths. The emergence of parasites resistant to available treatments makes the identification of new targets and their inhibitors an urgent task for the development of novel anti-malaria drugs. Protein kinase CK2 is an evolutionary-conserved eukaryotic serine/threonine protein kinase that in Plasmodium falciparum (PfCK2) has been characterized as a promising target for chemotherapeutic intervention against malaria. Here we report a crystallographic structure of the catalytic domain of PfCK2α (D179S inactive single mutant) in complex with ATP at a resolution of 3.0 Å. Compared to the human enzyme, the structure reveals a subtly altered ATP binding pocket comprising five substitutions in the vicinity of the adenine base, that together with potential allosteric sites, could be exploited to design novel inhibitors specifically targeting the Plasmodium enzyme. We provide evidence for the dual autophosphorylation of residues Thr63 and Tyr30 of PfCK2. We also show that CX4945, a human CK2 inhibitor in clinical trials against solid tumor cancers, is effective against PfCK2 with an IC50 of 13.2 nM.
Keyphrases
- plasmodium falciparum
- protein kinase
- crystal structure
- tyrosine kinase
- endothelial cells
- clinical trial
- induced pluripotent stem cells
- epidermal growth factor receptor
- randomized controlled trial
- small molecule
- pluripotent stem cells
- photodynamic therapy
- genome wide
- gene expression
- transcription factor
- binding protein
- young adults
- open label