Allosteric binding cooperativity in kinases signaling, signalopathies, and drug development

Protein kinases catalyze the transfer of phosphate groups from ATP to specific substrates, initiating, modulating, or terminating signaling cascades. Generally, the response of these enzymes to stimuli is characterized by ultrasensitive rather than graded responses and mediated by cooperative binding interactions. Here, we provide examples of positive and negative cooperativity processes regulating several protein kinases. We first examine the binding cooperativity between nucleotide and substrate in protein kinase A, showing how dysfunctional cooperativity may be linked to signalopathies. We then illustrate how certain drugs exploit cooperativity to inhibit kinase homo- and hetero-dimerization or select for active and inactive conformational states. A molecular understanding of binding cooperativity could lead to the development of new kinase-specific inhibitors, opening up novel therapeutic possibilities.