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

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 euk...

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Autores principales:	David Ruiz-Carrillo, Jianqing Lin, Abbas El Sahili, Meng Wei, Siu Kwan Sze, Peter C. F. Cheung, Christian Doerig, Julien Lescar
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/58ab85b505ca437a9526f9ae8fbfbcc3
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spelling	oai:doaj.org-article:58ab85b505ca437a9526f9ae8fbfbcc32021-12-02T16:08:13ZThe protein kinase CK2 catalytic domain from Plasmodium falciparum: crystal structure, tyrosine kinase activity and inhibition10.1038/s41598-018-25738-52045-2322https://doaj.org/article/58ab85b505ca437a9526f9ae8fbfbcc32018-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-25738-5https://doaj.org/toc/2045-2322Abstract 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.David Ruiz-CarrilloJianqing LinAbbas El SahiliMeng WeiSiu Kwan SzePeter C. F. CheungChristian DoerigJulien LescarNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-12 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q David Ruiz-Carrillo Jianqing Lin Abbas El Sahili Meng Wei Siu Kwan Sze Peter C. F. Cheung Christian Doerig Julien Lescar The protein kinase CK2 catalytic domain from Plasmodium falciparum: crystal structure, tyrosine kinase activity and inhibition
description	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 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.
format	article
author	David Ruiz-Carrillo Jianqing Lin Abbas El Sahili Meng Wei Siu Kwan Sze Peter C. F. Cheung Christian Doerig Julien Lescar
author_facet	David Ruiz-Carrillo Jianqing Lin Abbas El Sahili Meng Wei Siu Kwan Sze Peter C. F. Cheung Christian Doerig Julien Lescar
author_sort	David Ruiz-Carrillo
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
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/58ab85b505ca437a9526f9ae8fbfbcc3
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_version_	1718384596728414208

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

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