The protein kinase CK2 catalytic domain from Plasmodium falciparum : crystal structure, tyrosine kinase activity and inhibition
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 s...
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sg-ntu-dr.10356-868312023-02-28T17:01:50Z The protein kinase CK2 catalytic domain from Plasmodium falciparum : crystal structure, tyrosine kinase activity and inhibition Ruiz-Carrillo, David Lin, Jianqing El Sahili, Abbas Wei, Meng Sze, Siu Kwan Doerig, Christian Lescar, Julien Cheung, Peter Ching For School of Biological Sciences NTU Institute of Structural Biology Protein Kinase CK2 Malaria 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. MOE (Min. of Education, S’pore) Published version 2018-07-27T05:55:45Z 2019-12-06T16:29:50Z 2018-07-27T05:55:45Z 2019-12-06T16:29:50Z 2018 Journal Article Ruiz-Carrillo, D., Lin, J., El Sahili, A., Wei, M., Sze, S. K., Cheung, P. C. F., et al. (2018). The protein kinase CK2 catalytic domain from Plasmodium falciparum : crystal structure, tyrosine kinase activity and inhibition. Scientific Reports, 8(1), 7365-. 2045-2322 https://hdl.handle.net/10356/86831 http://hdl.handle.net/10220/45318 10.1038/s41598-018-25738-5 en Scientific Reports © 2018 The Author(s) (Nature Publishing Group). This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. 12 p. application/pdf |
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Protein Kinase CK2 Malaria Ruiz-Carrillo, David Lin, Jianqing El Sahili, Abbas Wei, Meng Sze, Siu Kwan Doerig, Christian Lescar, Julien Cheung, Peter Ching For The protein kinase CK2 catalytic domain from Plasmodium falciparum : crystal structure, tyrosine kinase activity and inhibition |
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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. |
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School of Biological Sciences |
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School of Biological Sciences Ruiz-Carrillo, David Lin, Jianqing El Sahili, Abbas Wei, Meng Sze, Siu Kwan Doerig, Christian Lescar, Julien Cheung, Peter Ching For |
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Article |
author |
Ruiz-Carrillo, David Lin, Jianqing El Sahili, Abbas Wei, Meng Sze, Siu Kwan Doerig, Christian Lescar, Julien Cheung, Peter Ching For |
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Ruiz-Carrillo, David |
title |
The protein kinase CK2 catalytic domain from Plasmodium falciparum : crystal structure, tyrosine kinase activity and inhibition |
title_short |
The protein kinase CK2 catalytic domain from Plasmodium falciparum : crystal structure, tyrosine kinase activity and inhibition |
title_full |
The protein kinase CK2 catalytic domain from Plasmodium falciparum : crystal structure, tyrosine kinase activity and inhibition |
title_fullStr |
The protein kinase CK2 catalytic domain from Plasmodium falciparum : crystal structure, tyrosine kinase activity and inhibition |
title_full_unstemmed |
The protein kinase CK2 catalytic domain from Plasmodium falciparum : crystal structure, tyrosine kinase activity and inhibition |
title_sort |
protein kinase ck2 catalytic domain from plasmodium falciparum : crystal structure, tyrosine kinase activity and inhibition |
publishDate |
2018 |
url |
https://hdl.handle.net/10356/86831 http://hdl.handle.net/10220/45318 |
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1759854826948132864 |