The protein kinase activity modulation sites: Mechanisms for cellular regulation - Targets for therapeutic intervention

Protein kinases catalyze the phosphoryl transfer reaction fundamental to most signaling and regulatory processes in the eukaryotic cell. The signaling reaction is covalent transfer of the gamma phosphoryl group of ATP, and in exceptional cases GTP, to threonine, serine, or tyrosine residues of the substrate protein. Each member of the huge protein kinase family has its individual cellular function and role; many or most phosphorylate more than one substrate protein. Thus, absolute control of individual protein kinase activity is of utmost importance to the cell. How this modulation, including complete but reversible inactivation, can be achieved has been shown by crystal structures of many active and inactive protein kinases. This article presents a survey of inactivated kinase structures, compared with the structures of active and catalytically competent kinases, such as protein kinase A catalytic subunit (PKAc) which demonstrates the repetitive occurrence of structural alterations in certain regions of the catalytic kinase core. These sites or elements, classified here as "activity modulation sites," comprise four structures: the activation segment with its continuation into the P + 1 region, helix C, the glycine rich flap, and the ATP-binding pocket. We address the question of whether these constitute the primary evolved mechanisms for modulation of enzyme activity in the catalytic domain, and thus represent the mechanisms operative for most other protein kinases and physiological regulators, and how this might impact strategies for discovery and design of therapeutic drugs.