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Allosteric Regulation of Protein Kinase PKCζ by the N-Terminal C1 Domain and Small Compounds to the PIF-Pocket

Abstract : 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 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.
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Submitted on : Wednesday, February 10, 2021 - 5:48:49 PM
Last modification on : Wednesday, March 31, 2021 - 3:23:46 AM

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Laura Lopez-Garcia, Jörg Schulze, Wolfgang Fröhner, Hua Zhang, Evelyn Süss, et al.. Allosteric Regulation of Protein Kinase PKCζ by the N-Terminal C1 Domain and Small Compounds to the PIF-Pocket. Chemistry and Biology, Elsevier, 2011, 18 (11), pp.1463-1473. ⟨10.1016/j.chembiol.2011.08.010⟩. ⟨pasteur-03137928⟩

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