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

Authors
 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 
Citation
 SCIENTIFIC REPORTS, Vol.9(1) : e14398, 2019 
Journal Title
SCIENTIFIC REPORTS
Issue Date
2019
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.
Files in This Item:
T201904043.pdf Download
DOI
10.1038/s41598-019-50678-z
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Microbiology (미생물학교실) > 1. Journal Papers
Yonsei Authors
Shin, Jeon Soo(신전수) ORCID logo https://orcid.org/0000-0002-8294-3234
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/173153
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