Conformational plasticity of the catalytic subunit of protein kinase CK2 and its consequences for regulation and drug design

At the first glance CK2 alpha, the catalytic subunit of protein kinase CK2, is a rigid molecule: in contrast to many eukaryotic protein kinases in CK2 alpha the canonical regulatory key elements like the activation segment occur exclusively in their typical active conformations. This observation fits well to the constitutive activity of the enzyme, meaning, its independence from phosphorylation or other characteristic control factors. Most CK2 alpha structures are based on the enzyme from Zea mays, supplemented by an increasing number of human CK2 alpha structures. In the latter a surprising plasticity of important ATP-binding elements - the interclomain hinge region and the glycine-rich loop - was discovered. in fully active CK2 alpha the hinge region is open and does not anchor the ATP ribose, but alternatively it can adopt a closed conformation, form hydrogen bonds to the ribose moiety and thus retract the -y-phospho group from its functional position. in addition to this partially inactive state human CK2 alpha was recently found in a fully inactive conformation. It is incompatible with ATPbinding due to a combination of a closed hinge and a collapse of the giycine-rich loop into the ATP cavity. These conformational transitions are apparently correlated with the occupation state of a remote docking site located at the interface to the non-cataiytic subunit CK2 beta: if CK2 beta blocks this site, the fully active conformation of CK2 alpha is stabilized, while the binding of certain small molecule seems to favour the partially and fully inactive states. This observation may be exploited to design effective and selective CK2 inhibitors. (C) 2009 Elsevier B.V. All rights reserved.