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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
Laura Lopez-Garcia
1
Jörg Schulze
1
Wolfgang Fröhner
2
Hua Zhang
1
Evelyn Süss
1
Nadja Weber
2
Jeanette Navratil
1
Sabine Amon
3
Valerie Hindie
1
Stefan Zeuzem
1
Thomas Jørgensen
3
Pedro Alzari
4
Sonja Neimanis
1
Matthias Engel
2
Ricardo Biondi
1, *
*
Corresponding author
Laura A. Lopez-Garcia 1
Author
Jörg O. Schulze 1
Author
Wolfgang Fröhner 2
Author
Hua Zhang 1
Author
Valerie Hindie 1
Author
Stefan Zeuzem 1
Author
Thomas J. D. Jørgensen 3
Author
Pedro M. Alzari 4
Author
1
Universitätsklinikum Frankfurt (Theodor-Stern-Kai 7
60590 Frankfurt - Germany)
2
Universität des Saarlandes [Saarbrücken] (Universität des Saarlandes Campus D-66123 Saarbrücken - Germany)
3
SDU - University of Southern Denmark (5320 Odense - Denmark)
4
Biochimie Structurale (28 Rue du Docteur Roux 75724 Paris Cedex 15 - France)
- CNRS - Centre National de la Recherche Scientifique : URA2185 (France)
- Institut Pasteur [Paris] (25-28, rue du docteur Roux, 75724 Paris cedex 15 - France)
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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https://hal-pasteur.archives-ouvertes.fr/pasteur-03137928
Contributor : Marie de Tarragon <>
Submitted on : Wednesday, February 10, 2021 - 5:48:49 PM
Last modification on : Wednesday, March 31, 2021 - 3:23:46 AM
Contributor : Marie de Tarragon <>
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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- HAL Id : pasteur-03137928, version 1
- DOI : 10.1016/j.chembiol.2011.08.010
- PUBMED : 22118680
Citation
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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