4UB7: High-salt Structure Of Protein Kinase Ck2 Catalytic Subunit With 4'- Carboxy-6,8-bromo-flavonol (flc26) Showing An Extreme Distortion Of The Atp-binding Loop Combined With A Pi-halogen Bond

Citation:
Abstract
CK2 is a Ser/Thr kinase recruited by tumor cells to avoid cell death. 4'-Carboxy-6,8-dibromo-flavonol (FLC26) is a nanomolar CK2 inhibitor reducing the physiological phosphorylation of CK2 biomarkers and inducing cell death. Its binding mode to the ATP site was predicted to depend primarily on noncovalent interactions not comprising halogen bonds. We confirm this by two independent cocrystal structures which additionally show that FLC26 is selective for an open, protein kinase-untypical conformation of the hinge/helix alphaD region. The structures suggest how the bromo substituents, found previously in lead optimization studies, contribute to the inhibitory efficacy. In this context, one of the complex structures, obtained by crystallization with the kosmotropic salt NaCl, revealed an unconventional pi-halogen bond between the 8-bromo substituent of FLC26 and an aromatic side chain which is absent under low-salt conditions. The kosmotropic salt sensitivity of pi-halogen bonds is a novel feature which requires attention in structural comparisons and halogen-bond-based explanations.
PDB ID: 4UB7Download
MMDB ID: 130498
PDB Deposition Date: 2014/8/12
Updated in MMDB: 2017/09
Experimental Method:
x-ray diffraction
Resolution: 2.1  Å
Source Organism:
Similar Structures:
Biological Unit for 4UB7: monomeric; determined by author and by software (PISA)
Molecular Components in 4UB7
Label Count Molecule
Protein (1 molecule)
1
Casein Kinase II Subunit Alpha(Gene symbol: CSNK2A1)
Molecule annotation
Chemicals (4 molecules)
1
1
2
3
* Click molecule labels to explore molecular sequence information.

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