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AGC protein kinases: from structural mechanism of regulation to allosteric drug development for the treatment of human diseases.
- Source :
-
Biochimica et biophysica acta [Biochim Biophys Acta] 2013 Jul; Vol. 1834 (7), pp. 1302-21. Date of Electronic Publication: 2013 Mar 21. - Publication Year :
- 2013
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Abstract
- The group of AGC protein kinases includes more than 60 protein kinases in the human genome, classified into 14 families: PDK1, AKT/PKB, SGK, PKA, PKG, PKC, PKN/PRK, RSK, NDR, MAST, YANK, DMPK, GRK and SGK494. This group is also widely represented in other eukaryotes, including causative organisms of human infectious diseases. AGC kinases are involved in diverse cellular functions and are potential targets for the treatment of human diseases such as cancer, diabetes, obesity, neurological disorders, inflammation and viral infections. Small molecule inhibitors of AGC kinases may also have potential as novel therapeutic approaches against infectious organisms. Fundamental in the regulation of many AGC kinases is a regulatory site termed the "PIF-pocket" that serves as a docking site for substrates of PDK1. This site is also essential to the mechanism of activation of AGC kinases by phosphorylation and is involved in the allosteric regulation of N-terminal domains of several AGC kinases, such as PKN/PRKs and atypical PKCs. In addition, the C-terminal tail and its interaction with the PIF-pocket are involved in the dimerization of the DMPK family of kinases and may explain the molecular mechanism of allosteric activation of GRKs by GPCR substrates. In this review, we briefly introduce the AGC kinases and their known roles in physiology and disease and the discovery of the PIF-pocket as a regulatory site in AGC kinases. Finally, we summarize the current status and future therapeutic potential of small molecules directed to the PIF-pocket; these molecules can allosterically activate or inhibit the kinase as well as act as substrate-selective inhibitors. This article is part of a Special Issue entitled: Inhibitors of Protein Kinases (2012).<br /> (Copyright © 2013 Elsevier B.V. All rights reserved.)
- Subjects :
- Allosteric Regulation
Candida albicans drug effects
Candida albicans enzymology
Candidiasis drug therapy
Candidiasis microbiology
Humans
Neoplasms drug therapy
Neoplasms enzymology
Phosphorylation drug effects
Protein Kinase Inhibitors pharmacology
Protein Kinases classification
Models, Molecular
Protein Kinases chemistry
Protein Kinases metabolism
Protein Structure, Tertiary
Subjects
Details
- Language :
- English
- ISSN :
- 0006-3002
- Volume :
- 1834
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Biochimica et biophysica acta
- Publication Type :
- Academic Journal
- Accession number :
- 23524293
- Full Text :
- https://doi.org/10.1016/j.bbapap.2013.03.010