The protein kinase CK2 catalytic domain from Plasmodium falciparum: crystal structure, tyrosine kinase activity and inhibition

• Published in: Scientific reports Vol. 8; no. 1; pp. 7365 - 12
• Main Authors: Ruiz-Carrillo, David, Lin, Jianqing, El Sahili, Abbas, Wei, Meng, Sze, Siu Kwan, Cheung, Peter C. F., Doerig, Christian, Lescar, Julien
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 09.05.2018; Nature Publishing Group; Nature Portfolio
• Subjects: 101/58; 631/45; 631/535/1266; 82/80; 82/83; Adenine; Allosteric properties; ATP; Casein kinase II; Clinical trials; Crystal structure; Drug development; Enzymes; Evolutionary conservation; Humanities and Social Sciences; Kinases; Malaria; multidisciplinary; Parasites; Plasmodium falciparum; Protein kinase C; Protein-serine/threonine kinase; Protein-tyrosine kinase; Proteins; Science; Science (multidisciplinary); Solid tumors; Vector-borne diseases
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-018-25738-5

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 ( Pf CK2) has been characterized as a promising target for chemotherapeutic intervention against malaria. Here we report a crystallographic structure of the catalytic domain of Pf CK2α (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 Thr 63 and Tyr 30 of Pf CK2. We also show that CX4945, a human CK2 inhibitor in clinical trials against solid tumor cancers, is effective against Pf CK2 with an IC 50 of 13.2 nM.