6K3L
Crystal structure of CX-4945 bound Cka1 from C. neoformans
Summary for 6K3L
| Entry DOI | 10.2210/pdb6k3l/pdb |
| Descriptor | CMGC/CK2 protein kinase, 5-[(3-chlorophenyl)amino]benzo[c][2,6]naphthyridine-8-carboxylic acid, SULFATE ION, ... (4 entities in total) |
| Functional Keywords | kinase, transferase |
| Biological source | Cryptococcus neoformans var. grubii serotype A (strain H99 / ATCC 208821 / CBS 10515 / FGSC 9487) |
| Total number of polymer chains | 1 |
| Total formula weight | 40026.80 |
| Authors | |
| Primary citation | Ong, B.X.,Yoo, Y.,Han, M.G.,Park, J.B.,Choi, M.K.,Choi, Y.,Shin, J.S.,Bahn, Y.S.,Cho, H.S. Structural analysis of fungal pathogenicity-related casein kinase alpha subunit, Cka1, in the human fungal pathogen Cryptococcus neoformans. Sci Rep, 9:14398-14398, 2019 Cited by PubMed 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-Mg (2.40 Å) and Cka1-CX-4945 (2.09 Å). Structural comparisons of Cka1-AMPPNP-Mg 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. PubMed: 31591414DOI: 10.1038/s41598-019-50678-z PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.09 Å) |
Structure validation
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