4a07

Publication Abstract from PubMed

Protein 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 PKCzeta 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 PKCzeta 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 PKCzeta activity. This work establishes a central role for the PIF-pocket on the regulation of PKCzeta and allows us to envisage development of drugs targeting the PIF-pocket that can either activate or inhibit AGC kinases.

Allosteric Regulation of Protein Kinase PKCzeta by the N-Terminal C1 Domain and Small Compounds to the PIF-Pocket.,Lopez-Garcia LA, Schulze JO, Frohner W, Zhang H, Suss E, Weber N, Navratil J, Amon S, Hindie V, Zeuzem S, Jorgensen TJ, Alzari PM, Neimanis S, Engel M, Biondi RM Chem Biol. 2011 Nov 23;18(11):1463-1473. PMID:22118680^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.