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.
Highlights
IntroductionProtein kinase CK2 (formerly known as casein kinase 2) is a constitutively active, ubiquitous and highly conserved serine/threonine kinase complex that lies within the CMGC group of protein kinases[1,2]
Protein kinase CK2 is a constitutively active, ubiquitous and highly conserved serine/threonine kinase complex that lies within the CMGC group of protein kinases[1,2]
Given the instability of the CK2α protein, structure-based research on CK2α is predominantly limited to Homo sapiens CK2α and Zea mays CK2α, many of which are in complex with other compounds
Summary
Protein kinase CK2 (formerly known as casein kinase 2) is a constitutively active, ubiquitous and highly conserved serine/threonine kinase complex that lies within the CMGC group of protein kinases[1,2]. CX-4945 is a selective inhibitor that harbours anti-tumour, anti-proliferative, and anti-angiogenic properties[14] It functions by suppressing the pro-survival cellular PI3K/AKT pathway and stimulating apoptosis in cancer cells[14], thereby exerting its effects on a variety of cancers and tumours such as advanced solid tumours and multiple myeloma[15]. CX-4945 is the only CK2 inhibitor that has entered human clinical trials (Phase II) for cholangiocarcinoma treatment (Senhwa Biosciences, Inc.; ClinicalTrials.gov Identifier: NCT02128282) This indicates its clinical potential in cancer therapeutics. The structures of S. cerevisiae Cka[1] (scCka1)[8] and Plasmodium falciparum CK2α (pfCK2α)[19] have been recently determined, there remains a void to be filled in regard to the function and activity of CK2α in other lower eukaryotes. To bridge the gap between cancer and fungal infections, as well as to gain an understanding of the mechanisms by which fungal orthologues function as compared to their human counterpart, we have chosen to work on the Cryptococcus neoformans CK2α orthologue, Cka[1] (cnCka1), for the current study
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