Arencibia José M, Pastor-Flores Daniel, Bauer Angelika F, Schulze Jörg O, Biondi Ricardo M
Research Group PhosphoSites, Department of Internal Medicine I, Universitätsklinikum Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany.
Biochim Biophys Acta. 2013 Jul;1834(7):1302-21. doi: 10.1016/j.bbapap.2013.03.010. Epub 2013 Mar 21.
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).
AGC蛋白激酶家族在人类基因组中包含60多种蛋白激酶，分为14个家族：PDK1、AKT/PKB、SGK、PKA、PKG、PKC、PKN/PRK、RSK、NDR、MAST、YANK、DMPK、GRK和SGK494。该家族在其他真核生物中也广泛存在，包括人类传染病的病原体。AGC激酶参与多种细胞功能，是治疗癌症、糖尿病、肥胖症、神经疾病、炎症和病毒感染等人类疾病的潜在靶点。AGC激酶的小分子抑制剂也可能具有作为抗感染生物新治疗方法的潜力。许多AGC激酶调节的基础是一个称为“PIF口袋”的调节位点，它作为PDK1底物的对接位点。该位点对于AGC激酶通过磷酸化激活的机制也至关重要，并参与几种AGC激酶（如PKN/PRKs和非典型PKCs）N端结构域的变构调节。此外，C端尾巴及其与PIF口袋的相互作用参与了DMPK激酶家族的二聚化，并可能解释GPCR底物对GRKs变构激活的分子机制。在本综述中，我们简要介绍了AGC激酶及其在生理学和疾病中的已知作用，以及PIF口袋作为AGC激酶调节位点的发现。最后，我们总结了针对PIF口袋的小分子的现状和未来治疗潜力；这些分子可以变构激活或抑制激酶，以及作为底物选择性抑制剂。本文是名为：蛋白激酶抑制剂（2012年）的特刊的一部分。
