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

ABSTRACT: CK2? 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 CK2? 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 CK2? 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 CK2?-CX-4945. Supporting it, in vitro kinase assay demonstrated that CX-4945 inhibited human CK2? much more efficiently than Cka1. Our results provide structural insights into the design of more selective inhibitors against Cka1.

SUBMITTER: Ong BX 

PROVIDER: S-EPMC6779870 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature