| Citation | Distinguished for his work defining the basis for protein substrate recognition by protein kinases and on the mechanism of intramolecular regulation of protein kinase activity. Using the cAMP?dependent protein kinase as a model system he was the first to show that protein kinases recognize their substrates via short primary sequences surrounding the target hydroxyamino acid. The cAMP?dependent protein kinase requires Arg.Arg.Xxx.Ser. Each of the other protein kinases he examined also has a distinct primary sequence specificity. He used this information to develop short peptide substrates for several protein kinases. One of these known as Kemptide is still widely used as a substrate for cAMP?dependent protein kinase. Based on these substrate sequence specificities he proposed a model for intramolecular regulation of protein kinase activity for several protein kinases in which the catalytic domain active site binds to a short "pseudosubstrate" sequence elsewhere in the protein, thus decreasing activity. He provided evidence that many protein kinases are negatively regulated by this type of intrasteric regulation, and convincingly proved this mechanism in the case of the twitchin protein kinase through analysis of its crystal structure. In summary, his research has been characterised by simple penetrating ideas on the fundamental mechanism involved in the regulation and function of protein kinases. |