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
Summary for 4UB7
| Entry DOI | 10.2210/pdb4ub7/pdb |
| Related | 1JWH |
| Descriptor | Casein kinase II subunit alpha, 4-(6,8-dibromo-3-hydroxy-4-oxo-4H-chromen-2-yl)benzoic acid, CHLORIDE ION, ... (4 entities in total) |
| Functional Keywords | protein kinase ck2, atp-competitive inhibitors, halogen bond, 4'-carboxy-6, 8-bromo-flavonol, transferase |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 40613.14 |
| Authors | Niefind, K.,Bischoff, N.,Guerra, B.,Golub, A.,Issinger, O.-G. (deposition date: 2014-08-12, release date: 2015-07-01, Last modification date: 2024-05-08) |
| Primary citation | Guerra, B.,Bischoff, N.,Bdzhola, V.G.,Yarmoluk, S.M.,Issinger, O.G.,Golub, A.G.,Niefind, K. A Note of Caution on the Role of Halogen Bonds for Protein Kinase/Inhibitor Recognition Suggested by High- And Low-Salt CK2 alpha Complex Structures. Acs Chem.Biol., 10:1654-1660, 2015 Cited by PubMed 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. PubMed: 25961323DOI: 10.1021/acschembio.5b00235 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.1 Å) |
Structure validation
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