Structural Basis for the Non-catalytic Functions of Protein Kinases

Protein kinases are known primarily for their ability to phosphorylate protein substrates, which constitutes an essential biological process. Recently, compelling evidence has accumulated that the functions of many protein kinases extend beyond phosphorylation and include an impressive spectrum of non-catalytic roles, such as scaffolding, allosteric regulation, or even protein-DNA interactions. How the conserved kinase fold shared by all metazoan protein kinases can accomplish these diverse tasks in a specific and regulated manner is poorly understood. In this review, we analyze the molecular mechanisms supporting phosphorylation-independent signaling by kinases and attempt to identify common and unique structural characteristics that enable kinases to perform non-catalytic functions. We also discuss how post-translational modifications, protein-protein interactions, and small molecules modulate these non-canonical kinase functions. Finally, we highlight current efforts in the targeted design of small-molecule modulators of non-catalytic kinase functions, a new pharmacological challenge for which structural considerations are more important than ever. •Many protein kinases signal through non-catalytic mechanisms•Kinase domain conformational changes often regulate non-catalytic kinase functions•Non-enzymatic functions of kinases can be modulated using small molecules The functions of protein kinases are not limited to phosphorylation, and many kinases signal through non-enzymatic mechanisms. Kung and Jura review known non-catalytic functions of kinases, analyze the molecular mechanisms underlying these functions, and discuss efforts to design small-molecule modulators of non-catalytic kinase signaling.