Specific kinase inhibition using peptides to target kinase-substrate docking

Anna D. Cunningham§, NIR QVIT§,*
§Equal contribution
*Corresponding author
Stanford University School of Medicine,
Department of Chemical and Systems Biology,
269 Campus Drive, Stanford, CA 94305-5174, USA


Protein phosphorylation is an essential post-translational modification in signal transduction. The vast number of human protein kinases (over 500) and potential phosphorylation sites (over 500,000) suggests that phosphorylation events must be highly specific and spatially and temporally regulated. However, the catalytic domain is highly conserved across all human kinases, making it difficult to develop specific kinase inhibitors. Multiple mechanisms have evolved that contribute to kinase-substrate specificity, including specific substrate phosphoacceptor sequences, allosteric interactions between kinase and substrate, and formation of complexes with scaffold and adaptor proteins. These kinase-substrate interactions present attractive targets for development of therapeutic drugs that specifically inhibit a desired phosphorylation event. This review focuses on known kinase-substrate docking interactions and the use of peptides to regulate them.


Phosphorylation, the most abundant post-translational modification in signal transduction, controls many aspects of cell fate, such as cell division, differentiation, and apoptosis. In numerous processes, phosphorylation acts as a molecular switch between physiological and pathological outcomes. It is a reversible modification, catalysed by protein kinases, in which the γ-phosphate group from ATP is transferred to amino acids with free hydroxyl (-OH) groups (in eukaryotes, these are usually serine, threonine or tyrosine). Protein kinases are one of the largest families of genes in eukaryotes, consisting of 518 genes, or almost 2% of human proteins (1). The basic structure of a kinase consists of a small N-terminal lobe of b-sheets, a larger C-terminal lobe of a-helices, and the ATP binding site in a cleft between the two lobes. In both basic research and drug discovery, kinases are common targets of modulation by chemical tools; however, the high conservation and similarity of ATP-binding pockets presents a tough challenge for the development of selective ATP-competitive inhibitors (Figure 1a).
One way to overcome this limitation i ...