Molecular Mechanism of Regulation of the Atypical Protein Kinase C by N-terminal Domains and an Allosteric Small Compound
Copyright policy )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.
- Goethe University Frankfurt Germany
- University of Southern Denmark Denmark
- University Hospital Frankfurt Germany
- Saarland University Germany
Pharmacology, Models, Molecular, Molecular Structure, Clinical Biochemistry, Biphenyl Compounds, Biochemistry, Protein Structure, Tertiary, Structure-Activity Relationship, Allosteric Regulation, Cinnamates, Drug Discovery, Molecular Medicine, Humans, Molecular Biology, Protein Kinase Inhibitors, Protein Kinase C
Pharmacology, Models, Molecular, Molecular Structure, Clinical Biochemistry, Biphenyl Compounds, Biochemistry, Protein Structure, Tertiary, Structure-Activity Relationship, Allosteric Regulation, Cinnamates, Drug Discovery, Molecular Medicine, Humans, Molecular Biology, Protein Kinase Inhibitors, Protein Kinase C
citations This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).22 popularity This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.Top 10% influence This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).Average impulse This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.Top 10%
Citations provided by BIP!Popularity provided by BIP!