Structural Studies of the Complex Between Akt-In and the Akt2-PH Domain Suggest That the Peptide Acts As an Allosteric Inhibitor of the Akt Kinase
The Open Spectroscopy Journal, 2009, 3, 65-76 65 Open Access Structural Studies of the Complex Between Akt-in and the Akt2-PH Domain Suggest that the Peptide Acts as an Allosteric Inhibitor of the Akt Kinase Virginie Ropars1,2,3, Philippe Barthe1,2,3, Chi-Shien Wang4, Wenlung Chen4, Der-Lii M. Tzou4,5, Anne Descours6, Loïc Martin6, Masayuki Noguchi7, Daniel Auguin1,2,3,,¶ and Christian Roumestand*,1,2,3 1CNRS UMR 5048, Centre de Biochimie Structurale, Montpellier, France 2INSERM U554, Montpellier, France 3Université Montpellier I et II, Montpellier, France 4Department of Applied Chemistry, National Chiayi University, Chiayi 60004, Taiwan, ROC 5Institute of Chemistry, Academia Sinica, Nankang, Taipei 11529, Taiwan, ROC 6CEA, iBiTecs, Service d’Ingénierie Moléculaire des Protéines, 91191 Gif sur Yvette, France 7Division of Cancer Biology, Institute for Genetic Medicine, Hokkaido University, N15 W7, Kita-ku, Sapporo 060-0815, Japan Abstract: Serine/threonine kinase Akt plays a central role in the regulation of cell survival and proliferation. Hence, the search for Akt specific inhibitors constitutes an attractive strategy for anticancer therapy. We have previously demonstrated that the proto-oncogene TCL1 coactivates Akt upon binding to its Plekstrin Homology Domain, and we proposed a model for the structure of the complex TCL1:Akt2-PHD. This model led to the rational design of Akt-in, a peptide inhibitor spanning the A ß-strand of human TCL1 that binds Akt2 PH domain and inhibits the kinase activation. In the present report, we used NMR spectroscopy to determine the 3D structure of the peptide free in solution and bound to Akt2-PHD.
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