ATP-conjugated peptide inhibitors for calmodulin-dependent protein kinase II

Substrate analog peptides of CaMKII with varying degrees of the inhibitory potency were linked to ATPγS either by considering a phosphoryl transfer mechanism or simply by using a relatively long flexible linker. The latter bisubstrate inhibitors showed relatively little effects while the former ones improved inhibitory potency to different levels depending on the binding affinities of the peptide moieties. One of the mechanism-based bisubstrate inhibitors was then utilized to demonstrate an ATP-competitive but peptide substrate-uncompetitive inhibition, supporting an ordered binding mechanism for CaMKII.

Graphical abstractConjugation of AIP peptide inhibitors to ATPγS by considering a phosphoryl transfer mechanism led to improved potency in CaMKII (calmodulin-dependent protein kinase II) inhibition, which was ATP-competitive and substrate-uncompetitive.Figure optionsDownload full-size imageDownload as PowerPoint slide