6FVF

The Structure of CK2alpha with CCh503 bound

Summary for 6FVF

• Entry DOI: 10.2210/pdb6fvf/pdb
• Descriptor: Casein kinase II subunit alpha, [1-[2-(phenylsulfonylamino)ethyl]piperidin-4-yl]methyl 5-fluoranyl-2-methoxy-1~{H}-indole-3-carboxylate, ADENOSINE-5'-TRIPHOSPHATE, ... (4 entities in total)
• Functional Keywords: ck2alpha, ck2a, fragment based drug discovery, high concentration screening, selective atp competitive inhibitors, surface entrophy reduction, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 40028.13

Authors

Brear, P.,Prudent, R.,Laudet, B.,Filhol, O.,Cochet, C.,Sautel, C.,Moucadel, V.,Bestgen, B.,Engel, M.,Ettaoussi, M.,Lomberget, T.,Le Borgne, M.,Kufareva, I.,Abagyan, R.,Hyvonen, M. (deposition date: 2018-03-02, release date: 2019-06-19, Last modification date: 2024-01-17)

Primary citation

Kufareva, I.,Bestgen, B.,Brear, P.,Prudent, R.,Laudet, B.,Moucadel, V.,Ettaoussi, M.,Sautel, C.F.,Krimm, I.,Engel, M.,Filhol, O.,Borgne, M.L.,Lomberget, T.,Cochet, C.,Abagyan, R.
Discovery of holoenzyme-disrupting chemicals as substrate-selective CK2 inhibitors.
Sci Rep, 9:15893-15893, 2019

PubMed Abstract: CK2 is a constitutively active protein kinase overexpressed in numerous malignancies. Interaction between CK2α and CK2β subunits is essential for substrate selectivity. The CK2α/CK2β interface has been previously targeted by peptides to achieve functional effects; however, no small molecules modulators were identified due to pocket flexibility and open shape. Here we generated numerous plausible conformations of the interface using the fumigation modeling protocol, and virtually screened a compound library to discover compound 1 that suppressed CK2α/CK2β interaction in vitro and inhibited CK2 in a substrate-selective manner. Orthogonal SPR, crystallography, and NMR experiments demonstrated that 4 and 6, improved analogs of 1, bind to CK2α as predicted. Both inhibitors alter CK2 activity in cells through inhibition of CK2 holoenzyme formation. Treatment with 6 suppressed MDA-MB231 triple negative breast cancer cell growth and induced apoptosis. Altogether, our findings exemplify an innovative computational-experimental approach and identify novel non-peptidic inhibitors of CK2 subunit interface disclosing substrate-selective functional effects.

PubMed: 31685885
DOI: 10.1038/s41598-019-52141-5

Experimental method

X-RAY DIFFRACTION (1.47 Å)