Structural analysis of fungal pathogenicity-related casein kinase α subunit, Cka1, in the human fungal pathogen Cryptococcus neoformans

Abstract CK2α is a constitutively active and highly conserved serine/threonine protein kinase that is involved in the regulation of key cellular metabolic pathways and associated with a variety of tumours and cancers. The most well-known CK2α inhibitor is the human clinical trial candidate CX-4945,...

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Autores principales:	Belinda X. Ong, Youngki Yoo, Myeong Gil Han, Jun Bae Park, Myung Kyung Choi, Yeseul Choi, Jeon-Soo Shin, Yong-Sun Bahn, Hyun-Soo Cho
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2019
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/53d7b32094a44078b4d9e5fef8d9f205
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spelling	oai:doaj.org-article:53d7b32094a44078b4d9e5fef8d9f2052021-12-02T15:09:20ZStructural analysis of fungal pathogenicity-related casein kinase α subunit, Cka1, in the human fungal pathogen Cryptococcus neoformans10.1038/s41598-019-50678-z2045-2322https://doaj.org/article/53d7b32094a44078b4d9e5fef8d9f2052019-10-01T00:00:00Zhttps://doi.org/10.1038/s41598-019-50678-zhttps://doaj.org/toc/2045-2322Abstract CK2α is a constitutively active and highly conserved serine/threonine protein kinase that is involved in the regulation of key cellular metabolic pathways and associated with a variety of tumours and cancers. The most well-known CK2α inhibitor is the human clinical trial candidate CX-4945, which has recently shown to exhibit not only anti-cancer, but also anti-fungal properties. This prompted us to work on the CK2α orthologue, Cka1, from the pathogenic fungus Cryptococcus neoformans, which causes life-threatening systemic cryptococcosis and meningoencephalitis mainly in immunocompromised individuals. At present, treatment of cryptococcosis remains a challenge due to limited anti-cryptococcal therapeutic strategies. Hence, expanding therapeutic options for the treatment of the disease is highly clinically relevant. Herein, we report the structures of Cka1-AMPPNP-Mg2+ (2.40 Å) and Cka1-CX-4945 (2.09 Å). Structural comparisons of Cka1-AMPPNP-Mg2+ with other orthologues revealed the dynamic architecture of the N-lobe across species. This may explain for the difference in binding affinities and deviations in protein-inhibitor interactions between Cka1-CX-4945 and human CK2α-CX-4945. Supporting it, in vitro kinase assay demonstrated that CX-4945 inhibited human CK2α much more efficiently than Cka1. Our results provide structural insights into the design of more selective inhibitors against Cka1.Belinda X. OngYoungki YooMyeong Gil HanJun Bae ParkMyung Kyung ChoiYeseul ChoiJeon-Soo ShinYong-Sun BahnHyun-Soo ChoNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 9, Iss 1, Pp 1-13 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Belinda X. Ong Youngki Yoo Myeong Gil Han Jun Bae Park Myung Kyung Choi Yeseul Choi Jeon-Soo Shin Yong-Sun Bahn Hyun-Soo Cho Structural analysis of fungal pathogenicity-related casein kinase α subunit, Cka1, in the human fungal pathogen Cryptococcus neoformans
description	Abstract CK2α is a constitutively active and highly conserved serine/threonine protein kinase that is involved in the regulation of key cellular metabolic pathways and associated with a variety of tumours and cancers. The most well-known CK2α inhibitor is the human clinical trial candidate CX-4945, which has recently shown to exhibit not only anti-cancer, but also anti-fungal properties. This prompted us to work on the CK2α orthologue, Cka1, from the pathogenic fungus Cryptococcus neoformans, which causes life-threatening systemic cryptococcosis and meningoencephalitis mainly in immunocompromised individuals. At present, treatment of cryptococcosis remains a challenge due to limited anti-cryptococcal therapeutic strategies. Hence, expanding therapeutic options for the treatment of the disease is highly clinically relevant. Herein, we report the structures of Cka1-AMPPNP-Mg2+ (2.40 Å) and Cka1-CX-4945 (2.09 Å). Structural comparisons of Cka1-AMPPNP-Mg2+ with other orthologues revealed the dynamic architecture of the N-lobe across species. This may explain for the difference in binding affinities and deviations in protein-inhibitor interactions between Cka1-CX-4945 and human CK2α-CX-4945. Supporting it, in vitro kinase assay demonstrated that CX-4945 inhibited human CK2α much more efficiently than Cka1. Our results provide structural insights into the design of more selective inhibitors against Cka1.
format	article
author	Belinda X. Ong Youngki Yoo Myeong Gil Han Jun Bae Park Myung Kyung Choi Yeseul Choi Jeon-Soo Shin Yong-Sun Bahn Hyun-Soo Cho
author_facet	Belinda X. Ong Youngki Yoo Myeong Gil Han Jun Bae Park Myung Kyung Choi Yeseul Choi Jeon-Soo Shin Yong-Sun Bahn Hyun-Soo Cho
author_sort	Belinda X. Ong
title	Structural analysis of fungal pathogenicity-related casein kinase α subunit, Cka1, in the human fungal pathogen Cryptococcus neoformans
title_short	Structural analysis of fungal pathogenicity-related casein kinase α subunit, Cka1, in the human fungal pathogen Cryptococcus neoformans
title_full	Structural analysis of fungal pathogenicity-related casein kinase α subunit, Cka1, in the human fungal pathogen Cryptococcus neoformans
title_fullStr	Structural analysis of fungal pathogenicity-related casein kinase α subunit, Cka1, in the human fungal pathogen Cryptococcus neoformans
title_full_unstemmed	Structural analysis of fungal pathogenicity-related casein kinase α subunit, Cka1, in the human fungal pathogen Cryptococcus neoformans
title_sort	structural analysis of fungal pathogenicity-related casein kinase α subunit, cka1, in the human fungal pathogen cryptococcus neoformans
publisher	Nature Portfolio
publishDate	2019
url	https://doaj.org/article/53d7b32094a44078b4d9e5fef8d9f205
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Structural analysis of fungal pathogenicity-related casein kinase α subunit, Cka1, in the human fungal pathogen Cryptococcus neoformans

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