Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
1391921 | Chemistry & Biology | 2011 | 11 Pages |
SummaryProtein kinases are key mediators of cellular signaling, and therefore, their activities are tightly controlled. AGC kinases are regulated by phosphorylation and by N- and C-terminal regions. Here, we studied the molecular mechanism of inhibition of atypical PKCζ and found that the inhibition by the N-terminal region cannot be explained by a simple pseudosubstrate inhibitory mechanism. Notably, we found that the C1 domain allosterically inhibits PKCζ activity and verified an allosteric communication between the PIF-pocket of atypical PKCs and the binding site of the C1 domain. Finally, we developed low-molecular-weight compounds that bind to the PIF-pocket and allosterically inhibit PKCζ activity. This work establishes a central role for the PIF-pocket on the regulation of PKCζ and allows us to envisage development of drugs targeting the PIF-pocket that can either activate or inhibit AGC kinases.
► C1 domain allosterically inhibits the activity of the catalytic domain of PKCζ ► There is an allosteric communication between C1 domain and the PIF-pocket ► Small compounds that bind to the PIF-pocket allosterically inhibit PKCζ activity ► The PIF-pocket is a pharmacological target for activators and inhibitors of AGC kinases