Page 14 - U. Protein structure and function

[U. Protein structure and function-10]

Protein structure of fungal pathogenicity-related casein

kinase a subunit, Ckα1, in the human fungal pathogen

Cryptococcus neoformans

Belinda Ong¹, Youngki Yoo¹, Myung Kyung Choi¹, Hyun-Soo Cho¹˙*

¹Systems Biology, Yonsei University, Seoul 03722, South Korea

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 anticryptococcal 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. Our results provide

structural insights into the design of more selective inhibitors against Cka1.