The protein kinase CK2 catalytic domain from Plasmodium falciparum: crystal structure, tyrosine kinase activity and inhibition
David Ruiz Carrillo, Jianqing Lin, Abbas El Sahili, Meng Wei, Siu Kwan Sze, Peter Cheung, Christian Doerig, Julien Lescar · Scientific Reports · 2018
Abstract 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 inPlasmodium falciparum(PfCK2) has been characterized as a promising target for chemotherapeutic intervention against malaria. Here we report a crystallographic structure of the catalytic domain ofPfCK2α (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 thePlasmodiumenzyme. We provide evidence for the dual autophosphorylation of residues Thr63and Tyr30ofPfCK2. We also show that CX4945, a human CK2 inhibitor in clinical trials against solid tumor cancers, is effective againstPfCK2 with an IC50of 13.2 nM.