Fig. 2: Crystal structure of 108600 in complex with CK2α. | Nature Communications

Fig. 2: Crystal structure of 108600 in complex with CK2α.

From: Simultaneous CK2/TNIK/DYRK1 inhibition by 108600 suppresses triple negative breast cancer stem cells and chemotherapy-resistant disease

Fig. 2

A Chemical structure of 108600. B Overall structure of the CK2α1-108600 complex. CK2α1 protein (pink) is shown in cartoon. 108600 is shown in sticks. A simulated annealing Fo-Fc omit electron density map for 108600 (green) is contoured at 3.0 σ-level at 1.80 Å resolution. C Zoom-in view of 108600 interactions with CK2α1. The water molecule (wat1) is shown as a red sphere. The electron density for the 2,6-dichlorobenzyl ring of the drug is disordered due to the conformational flexibility of this aromatic moiety in the solvent-exposed region of the active site; D A close-up view of 108600 interactions with CK2α1 depicting a surface view of the drug. E, F AMP-PNP (PDB ID: 3NSZ)21 (the γ-phosphate of AMP-PNP is hydrolyzed due to the acidic crystallization conditions to yield AMP-PN) and GMP-PNP (PDB ID: 1DAY)22 accommodations within the active site of CK2α1. The water-mediated ligand–protein interactions are also shown. G 108600, AMP-PN, and GMP-PNP in surface representation in the active site of CK2α1. Significantly, the drug mimics not only the shape and electrostatics of AMP-PN and GMP-PNP, but also their hydration patterns. H–J 108600 induces change in the conformation of the β4-β5 loop, which interacts with the regulatory CK2β subunit in the holoenzyme complex. H Superposition of CK2α1 structures with AMP-PNP alone (PDB ID: 3NSZ, beige) and integrated in the holoenzyme complex with CK2β regulatory subunit dimer (PDB ID: 1JWH, cyan)23, CK2α1 in the absence of ligand (PDB ID: 1NAZ, blue), and CK2α1 with 108600 (pink). Black frame highlights the β4-β5 loop. I CK2 kinase holoenzyme (PDB ID: 1JWH) and CK2α1-108600 complex. The holoenzyme consists of the two CK2α1 subunits (cyan) and the two CK2β regulatory subunits (green). CK2α1 subunit of the holoenzyme contains AMP-PNP. The CK2α1 β4-β5 loop region and its interaction with the loop of the CK2β subunit are highlighted by a thick black frame. J The “closed” conformation of the β4–β5 loop in the CK2α1/108600 complex (pink) appears to interfere with interactions with the loop of the CK2β subunit (green–blue) in the CK2 holoenzyme2.

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