Structural bases of protein kinase CK2 function and inhibition.

CK2, a member of the family of eukaryotic protein kinases (ePK), is ubiquitously present in eukaryotic cells and essential for their viability. With hundreds of sub- strates, the enzyme is implicated in many fundamental cellular processes. in particular, it is essential for cellular homeostasis: downregulation of CK2 leads to apoptosis, and abnormal over-activation has been found coupled to several diseases, in particular to cancer. the mechanism of regulation of CK2 is not firmly established yet; however, it is clear that it differs from those commonly utilized by other protein kinases. almost 15 years of intense crystallographic efforts, with dozens of crystal structures determined, have disclosed the structural bases of many key biochemical and functional properties of this enzyme. in this chapter, we review the progression in the structural biology of CK2 from the early discoveries to the current knowledge, giving our reasoned view of the state-of-art knowledge of the field. the basic structural features of the main CK2 entities—the catalytic subunit CK2α, the regulatory subunit CK2β, and the tetrameric α2β2 CK2 holoenzyme—are analyzed, in the broader context of the eukaryotic protein kinase family. from such an analysis, the picture of an anomalous protein kinase, “challenging the canons” proper of the vast majority of ePKs, clearly emerges. We further examine the issue of CK2 inhibition, a field fostered particularly by the involvement of CK2 in many pathologies and part of the wider topic of protein kinases inhibition, of particular interest for both the academia and pharmaceutical companies. Principles of CK2 inhibition by type I ATP-competitive inhibitors are now well established, and are reviewed and analyzed by means of several examples. the current state in the development of non-ATP-competitive inhibitors, which is very promising but still in an immature state, is also examined. alongside the critical review of the established knowledge, we finally address the still open questions, the perspectives, and the possible forthcoming developments in the field of CK2 structural biology.