Substrate-selective inhibition of protein kinase PDK1 by small compounds that bind to the PIF-pocket allosteric docking site
Articolo
Data di Pubblicazione:
2012
Citazione:
Substrate-selective inhibition of protein kinase PDK1 by small compounds that bind to the PIF-pocket allosteric docking site / K. Busschots, L.A. Lopez-Garcia, C. Lammi, A. Stroba, S. Zeuzem, A. Piiper, P.M. Alzari, S. Neimanis, J.M. Arencibia, M. Engel, J.O. Schulze, R.M. Biondi. - In: CHEMISTRY & BIOLOGY. - ISSN 1074-5521. - 19:9(2012 Sep 21), pp. 1152-1163.
Abstract:
The PIF-pocket of AGC protein kinases participates in the physiologic mechanism of regulation by acting as a docking site for substrates and as a switch for the transduction of the conformational changes needed for activation or inhibition. We describe the effects of compounds that bind to the PIF-pocket of PDK1. In vitro, PS210 is a potent activator of PDK1, and the crystal structure of the PDK1-ATP-PS210 complex shows that PS210 stimulates the closure of the kinase domain. However, in cells, the prodrug of PS210 (PS423) acts as a substrate-selective inhibitor of PDK1, inhibiting the phosphorylation and activation of S6K, which requires docking to the PIF-pocket, but not affecting PKB/Akt. This work describes a tool to study the dynamics of PDK1 activity and a potential approach for drug discovery.
Tipologia IRIS:
01 - Articolo su periodico
Elenco autori:
K. Busschots, L.A. Lopez-Garcia, C. Lammi, A. Stroba, S. Zeuzem, A. Piiper, P.M. Alzari, S. Neimanis, J.M. Arencibia, M. Engel, J.O. Schulze, R.M. Biondi
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