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Reports
Structural Basis for the Modulation of CDK-Dependent/Independent Activity of Cyclin D1
Jean-Luc Ferrer, Jerome Dupuy, Franck Borel, Lilian Jacquamet, Joseph P. Noel and Vjekoslav Dulic
volume 5 | issue 23
1 december 2006Pages: 2760 - 2768
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D-type cyclins are key regulators of the cell division cycle. In association with Cyclin Dependent Kinases (CDK) 2/4/6, they control the G1/S-phase transition in part by phosphorylation and inactivation of tumor suppressor of retinoblastoma family. Defective regulation of the G1/S transition is a well-known cause of cancer, making the cyclin D1-CDK4/6 complex a promising therapeutic target. Our objective is to develop inhibitors that would block the formation or the activation of the cyclin D1-CDK4/6 complex, using in silico docking experiments on a structural homology model of the cyclin D1-CDK4/6 complex. To this end we focused on the cyclin subunit in three different ways: (i) targeting the part of the cyclin D1 facing the N-terminal domain of CDK4/6, in order to prevent the dimer formation; (ii) targeting the part of the cyclin D1 facing the C-terminal domain of CDK4/6, in order to prevent the activation of CDK4/6 by blocking the T-loop in an inactive conformation, and also to destabilize the dimer; (iii) targeting the groove of cyclin D1 where p21 binds, in order to mimic its inhibition mode by preventing binding of cyclin D1-CDK4/6 complex to its targets. Our strategy, and the tools we developed, will provide a computational basis to design lead compounds for novel cancer therapeutics, targeting a broad range of proteins involved in the regulation of the cell cycle.
Authors
Jean-Luc Ferrer
Institut de Biologie Structural; Grenoble, France
Jerome Dupuy
Institut de Biologie Structural; Grenoble, France
Franck Borel
Institut de Biologie Structural; Grenoble, France
Lilian Jacquamet
Institut de Biologie Structural; Grenoble, France
Joseph P. Noel
Howard Hughes Medical Institute, Seattle, Washington
Vjekoslav Dulic
Centre National de la Recherche Scientifique, Montpellier, France
We now provide open access to journal articles published online for one year or more. This article may be downloaded at the following link:
Download PDF If the document does not open, please right-click on the link (control-click on a Macintosh) and select the option to save the file to disk.