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A Note of Caution on the Role of Halogen Bonds for Protein Kinase/Inhibitor Recognition Suggested by High- And Low-Salt CK2α Complex Structures.
- Source :
-
ACS chemical biology [ACS Chem Biol] 2015 Jul 17; Vol. 10 (7), pp. 1654-60. Date of Electronic Publication: 2015 May 15. - Publication Year :
- 2015
-
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 αD 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 π-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 π-halogen bonds is a novel feature which requires attention in structural comparisons and halogen-bond-based explanations.
- Subjects :
- Adenosine Triphosphate metabolism
Casein Kinase II antagonists & inhibitors
Casein Kinase II chemistry
Casein Kinase II metabolism
Catalytic Domain
Crystallography, X-Ray
Halogenation
Humans
Molecular Docking Simulation
Protein Conformation
Protein Structure, Secondary
Salts chemistry
Protein Kinase Inhibitors chemistry
Protein Kinase Inhibitors pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1554-8937
- Volume :
- 10
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- ACS chemical biology
- Publication Type :
- Academic Journal
- Accession number :
- 25961323
- Full Text :
- https://doi.org/10.1021/acschembio.5b00235