Molecular mechanism of regulation of the atypical protein kinase C by N-terminal domains and an allosteric small compound.
Protein kinases play important regulatory roles in cells and organisms. Therefore, they are subject to specific and tight mechanisms of regulation that ultimately converge on the catalytic domain and allow the kinases to be activated or inhibited only upon the appropriate stimuli. AGC protein kinases have a pocket in the catalytic domain, the PDK1-interacting fragment (PIF)-pocket, which is a key mediator of the activation. We show here that helix αC within the PIF-pocket of atypical protein kinase C (aPKC) is the target of the interaction with its inhibitory N-terminal domains. We also provide structural evidence that the small compound PS315 is an allosteric inhibitor that binds to the PIF-pocket of aPKC. PS315 exploits the physiological dynamics of helix αC for its binding and allosteric inhibition. The results will support research on allosteric mechanisms and selective drug development efforts against PKC isoforms.
Research Group PhosphoSites, Department of Internal Medicine I, Universitätsklinikum Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany.
Hua
H
Zhang
Research Group PhosphoSites, Department of Internal Medicine I, Universitätsklinikum Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany.
Sonja
S
Neimanis
Research Group PhosphoSites, Department of Internal Medicine I, Universitätsklinikum Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany.
Laura A
LA
Lopez-Garcia
Research Group PhosphoSites, Department of Internal Medicine I, Universitätsklinikum Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany.
José M
JM
Arencibia
Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark.
Sabine
S
Amon
Department of Pharmaceutical and Medicinal Chemistry, University of Saarland, 66041 Saarbrücken, Germany.
Adriana
A
Stroba
Research Group PhosphoSites, Department of Internal Medicine I, Universitätsklinikum Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany.
Stefan
S
Zeuzem
Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, 60438 Frankfurt, Germany.
Ewgen
E
Proschak
Research Group PhosphoSites, Department of Internal Medicine I, Universitätsklinikum Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany; Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, 60438 Frankfurt, Germany.
Holger
H
Stark
Research Group PhosphoSites, Department of Internal Medicine I, Universitätsklinikum Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany.
Angelika F
AF
Bauer
Research Group PhosphoSites, Department of Internal Medicine I, Universitätsklinikum Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany.
Katrien
K
Busschots
Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark.
Thomas J D
TJ
Jørgensen
Department of Pharmaceutical and Medicinal Chemistry, University of Saarland, 66041 Saarbrücken, Germany.
Matthias
M
Engel
Research Group PhosphoSites, Department of Internal Medicine I, Universitätsklinikum Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany.
Jörg O
JO
Schulze
Research Group PhosphoSites, Department of Internal Medicine I, Universitätsklinikum Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany. Electronic address: biondi@med.uni-frankfurt.de.
Ricardo M
RM
Biondi
D000494:Allosteric Regulation / Q000187:drug effects; D001713:Biphenyl Compounds / Q000737:chemistry / Q000494:pharmacology*; D002934:Cinnamates / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D017434:Protein Structure, Tertiary / Q000187:drug effects; D013329:Structure-Activity Relationship
D001713:Biphenyl Compounds; D002934:Cinnamates; C000596358:PS315; D047428:Protein Kinase Inhibitors; C115015:PKC-3 protein; D011493:Protein Kinase C