title: 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.
authors: Research Group PhosphoSites, Department of Internal Medicine I, Universitätsklinikum Frankfurt, 60590 Frankfurt, Germany.
authors: Laura A
authors: LA
authors: Lopez-Garcia
authors: Jörg O
authors: JO
authors: Schulze
authors: Wolfgang
authors: W
authors: Fröhner
authors: Hua
authors: H
authors: Zhang
authors: Evelyn
authors: E
authors: Süss
authors: Nadja
authors: N
authors: Weber
authors: Jeanette
authors: J
authors: Navratil
authors: Sabine
authors: S
authors: Amon
authors: Valerie
authors: V
authors: Hindie
authors: Stefan
authors: S
authors: Zeuzem
authors: Thomas J D
authors: TJ
authors: Jørgensen
authors: Pedro M
authors: PM
authors: Alzari
authors: Sonja
authors: S
authors: Neimanis
authors: Matthias
authors: M
authors: Engel
authors: Ricardo M
authors: RM
authors: Biondi
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D001665:Binding Sites; D055162:Biocatalysis; D045744:Cell Line, Tumor; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism; D011493:Protein Kinase C / Q000737:chemistry* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology; D000099221:Protein Kinase C zeta
chemical_list: D016328:NF-kappa B; D011493:Protein Kinase C; D054852:Small Molecule Libraries; D000099221:Protein Kinase C zeta