Structural highlights
Publication Abstract from PubMedp38alpha mitogen-activated protein kinase (MAPK) is generally activated by dual phosphorylation but has also been shown to exhibit alternative activation modes. One of these modes included a direct interaction with phosphatidylinositol ether lipid analogues (PIA) inducing p38alpha autoactivation and apoptosis. Perifosine, an Akt inhibitor in phase II clinical trials, also showed p38alpha activation properties similarly to those of PIAs. The crystal structures of p38alpha in complex with PIA23, PIA24 and perifosine provide insights into this unique activation mode. The activating molecules bind a unique hydrophobic binding site in the kinase C'-lobe formed in part by the MAPK insert region. In addition, there are conformational changes in the short alphaEF/alphaF loop region that acts as an activation switch, inducing autophosphorylation. Structural and biochemical characterization of the alphaEF/alphaF loop identified Trp197 as a key residue in the lipid binding and in p38alpha catalytic activity. The lipid binding site also accommodates hydrophobic inhibitor molecules and, thus, can serve as a novel p38alpha-target for specific activation or inhibition, with novel therapeutic implications. Lipid molecules induce p38alpha activation via a novel molecular switch.,Tzarum N, Eisenberg-Domovich Y, Gills JJ, Dennis PA, Livnah O J Mol Biol. 2012 Dec 14;424(5):339-53. doi: 10.1016/j.jmb.2012.10.007. Epub 2012 , Oct 16. PMID:23079240[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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