Looking lively: emerging principles of pseudokinase signaling.

Progress towards understanding catalytically 'dead' protein kinases – pseudokinases – in biology and disease has hastened over the past decade. An especially lively area for structural biology, pseudokinases appear to be strikingly similar to their kinase relatives, despite lacking key catalytic residues. Distinct active- and inactive-like conformation states, which are crucial for regulating bona fide protein kinases, are conserved in pseudokinases and appear to be essential for function. We discuss recent structural data on conformational transitions and nucleotide binding by pseudokinases, from which some common principles emerge. In both pseudokinases and bona fide kinases, a conformational toggle appears to control the ability to interact with signaling effectors. We also discuss how biasing this conformational toggle may provide opportunities to target pseudokinases pharmacologically in disease. Approximately 10% of proteins (58) in the human kinome are pseudokinases: they display the protein kinase fold but lack key conserved residues or have been observed experimentally to lack protein kinase activity. Several pseudokinases are implicated in human diseases, making them potential drug targets. A few domains first thought to qualify as pseudokinases retain kinase activity through compensatory changes, or have alternative catalytic activities. Many pseudokinases have compensatory mutations that allow retained ATP binding, despite being inactive kinases. Like their bona fide kinase relatives, several pseudokinases toggle conformationally between active-like and inactive-like states, and this controls their ability to interact with signaling effectors – suggesting analogies to regulation by small G proteins. Insights into conformation-dependent signaling by pseudokinases set the stage for their pharmacological targeting with conformational disruptors, and one pseudokinase-binding small molecule (targeting TYK2) is now in clinical development. [ABSTRACT FROM AUTHOR]