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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...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5943518/ https://www.ncbi.nlm.nih.gov/pubmed/29743645 http://dx.doi.org/10.1038/s41598-018-25738-5 |
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author | Ruiz-Carrillo, David Lin, Jianqing El Sahili, Abbas Wei, Meng Sze, Siu Kwan Cheung, Peter C. F. Doerig, Christian Lescar, Julien |
author_facet | Ruiz-Carrillo, David Lin, Jianqing El Sahili, Abbas Wei, Meng Sze, Siu Kwan Cheung, Peter C. F. Doerig, Christian Lescar, Julien |
author_sort | Ruiz-Carrillo, David |
collection | PubMed |
description | 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 Thr(63) and Tyr(30) of PfCK2. We also show that CX4945, a human CK2 inhibitor in clinical trials against solid tumor cancers, is effective against PfCK2 with an IC(50) of 13.2 nM. |
format | Online Article Text |
id | pubmed-5943518 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-59435182018-05-14 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 Cheung, Peter C. F. Doerig, Christian Lescar, Julien Sci Rep Article 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 Thr(63) and Tyr(30) of PfCK2. We also show that CX4945, a human CK2 inhibitor in clinical trials against solid tumor cancers, is effective against PfCK2 with an IC(50) of 13.2 nM. Nature Publishing Group UK 2018-05-09 /pmc/articles/PMC5943518/ /pubmed/29743645 http://dx.doi.org/10.1038/s41598-018-25738-5 Text en © The Author(s) 2018 Open Access 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/. |
spellingShingle | Article Ruiz-Carrillo, David Lin, Jianqing El Sahili, Abbas Wei, Meng Sze, Siu Kwan Cheung, Peter C. F. Doerig, Christian Lescar, Julien The protein kinase CK2 catalytic domain from Plasmodium falciparum: crystal structure, tyrosine kinase activity and inhibition |
title | 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_short | 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 |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5943518/ https://www.ncbi.nlm.nih.gov/pubmed/29743645 http://dx.doi.org/10.1038/s41598-018-25738-5 |
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