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Title
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Diacritic Binding of an Indenoindole Inhibitor by CK2α Paralogs Explored by a Reliable Path to Atomic Resolution CK2α' Structures.
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Authors
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D.Lindenblatt,
A.Nickelsen,
V.M.Applegate,
J.Hochscherf,
B.Witulski,
Z.Bouaziz,
C.Marminon,
M.Bretner,
M.Le Borgne,
J.Jose,
K.Niefind.
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Ref.
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ACS Omega, 2019,
4,
5471-5478.
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PubMed id
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Abstract
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CK2α and CK2α' are the two isoforms of the catalytic subunit of human protein
kinase CK2, an important target for cancer therapy. They have similar, albeit
not identical functional and structural properties, and were occasionally
reported to be inhibited with distinct efficacies by certain ATP-competitive
ligands. Here, we present THN27, an indeno[1,2-b]indole derivative, as a
further inhibitor with basal isoform selectivity. The selectivity disappears
when measured using CK2α/CK2α' complexes with CK2β, the regulatory CK2
subunit. Co-crystal structures of THN27 with CK2α and CK2α' reveal that subtle
differences in the conformational variability of the interdomain hinge region
are correlated with the observed effect. In the case of CK2α', a
crystallographically problematic protein so far, this comparative structural
analysis required the development of an experimental strategy that finally
enables atomic resolution structure determinations with ab initio phasing of
potentially any ATP-competitive CK2 inhibitor and possibly many
non-ATP-competitive ligands as well bound to CK2α'.
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