The monoclinic CK2α/heparin structure, in which the heparin fragment is particularly well defined, is the first CK2 structure with an anionic inhibitor of considerable size at the central part of the substrate-recognition site. Together, the structures rationalize the inhibitory efficacy of heparin fragments as a function of chain length. In the tetragonal structure, the heparin molecule binds to the polybasic stretch at the beginning of CK2α′s helix αC, whereas in the monoclinic structure it occupies the central substrate-recognition region around the P+1 loop. Here, a tetragonal and a monoclinic co-crystal structure of CK2α, the catalytic subunit of CK2, with a decameric heparin fragment are described. The structural basis of CK2’s preference for anionic substrates and substrate-competitive inhibitors is only vaguely known which limits the value of the substrate-binding region for the structure-based development of CK2 bisubstrate inhibitors. The latter, a highly sulphated glucosamino glycan composed mainly of repeating 2- O-sulpho-α- l-idopyranuronic acid/ N,O6-disulpho-α- d-glucosamine disaccharide units, is the longest known substrate-competitive CK2 inhibitor.
The Ser/Thr kinase CK2, a member of the superfamily of eukaryotic protein kinases, has an acidophilic substrate profile with the substrate recognition sequence S/T-D/E-X-D/E, and it is inhibited by polyanionic substances like heparin.
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