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Journal articles
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.
https://hal-pasteur.archives-ouvertes.fr/pasteur-03137928
Contributor : Marie de TARRAGON Connect in order to contact the contributor
Submitted on : Wednesday, February 10, 2021 - 5:48:49 PM
Last modification on : Thursday, April 7, 2022 - 10:10:29 AM
Contributor : Marie de TARRAGON Connect in order to contact the contributor
Submitted on : Wednesday, February 10, 2021 - 5:48:49 PM
Last modification on : Thursday, April 7, 2022 - 10:10:29 AM
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