4U7H

Oxidized quinone reductase 2 in complex with CK2 inhibitor DMAT

Summary for 4U7H

• Entry DOI: 10.2210/pdb4u7h/pdb
• Related: 4U7F 4U7G
• Descriptor: Ribosyldihydronicotinamide dehydrogenase [quinone], ZINC ION, FLAVIN-ADENINE DINUCLEOTIDE, ... (5 entities in total)
• Functional Keywords: reduced quinone reductase 2, dmat, oxidoreductase-inhibitor complex, oxidoreductase/inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm: P16083
• Total number of polymer chains: 2
• Total formula weight: 54354.17

Authors

Leung, K.K.,Shilton, B.H. (deposition date: 2014-07-30, release date: 2015-02-11, Last modification date: 2023-12-27)

Primary citation

Leung, K.K.,Shilton, B.H.
Quinone Reductase 2 Is an Adventitious Target of Protein Kinase CK2 Inhibitors TBBz (TBI) and DMAT.
Biochemistry, 54:47-59, 2015

PubMed Abstract: Quinone reductase 2 (NQO2) exhibits off-target interactions with two protein kinase CK2 inhibitors, 4,5,6,7-1H-tetrabromobenzimidazole (TBBz) and 2-dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole (DMAT). TBBz and DMAT induce apoptosis in cells expressing an inhibitor-resistant CK2, suggesting that the interaction with NQO2 may mediate some of their pharmacological effects. In this study, we have fully characterized the binding of TBBz and DMAT to NQO2. Fluorescence titrations showed that TBBz and DMAT bind oxidized NQO2 in the low nanomolar range; in the case of TBBz, the affinity for NQO2 was 40-fold greater than its affinity for CK2. A related CK2 inhibitor, 4,5,6,7-tetrabromobenzotriazole (TBB), which failed to cause apoptosis in cells expressing inhibitor-resistant CK2, binds NQO2 with an affinity 1000-fold lower than those of TBBz and DMAT. Kinetic analysis indicated that DMAT inhibits NQO2 by binding with similar affinities to the oxidized and reduced forms. Crystal structure analysis showed that DMAT binds reduced NQO2 in a manner different from that in the oxidized state. In oxidized NQO2, TBBz and DMAT are deeply buried in the active site and make direct hydrogen and halogen bonds to the enzyme. In reduced NQO2, DMAT occupies a more peripheral region and hydrogen and halogen bonds with the enzyme are mediated through three water molecules. Therefore, although TBB, TBBz, and DMAT are all potent inhibitors of CK2, they exhibit different activity profiles toward NQO2. We conclude that the active site of NQO2 is fundamentally different from the ATP binding site of CK2 and the inhibition of NQO2 by CK2 inhibitors is adventitious.

PubMed: 25379648
DOI: 10.1021/bi500959t

Experimental method

X-RAY DIFFRACTION (1.48 Å)