6K3L

Crystal structure of CX-4945 bound Cka1 from C. neoformans

6K3L の概要

• エントリーDOI: 10.2210/pdb6k3l/pdb
• 分子名称: CMGC/CK2 protein kinase, 5-[(3-chlorophenyl)amino]benzo[c][2,6]naphthyridine-8-carboxylic acid, SULFATE ION, ... (4 entities in total)
• 機能のキーワード: kinase, transferase
• 由来する生物種: Cryptococcus neoformans var. grubii serotype A (strain H99 / ATCC 208821 / CBS 10515 / FGSC 9487)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 40026.80

構造登録者

Cho, H.S.,Yoo, Y. (登録日: 2019-05-20, 公開日: 2019-11-06, 最終更新日: 2023-11-22)

主引用文献

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

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: 31591414
DOI: 10.1038/s41598-019-50678-z

実験手法

X-RAY DIFFRACTION (2.09 Å)