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Interaction Between the Cdk2/Cyclin A Complex and a Small Molecule Derived from the pRb2/p130 Spacer Domain: A Theoretical Model

Antonio Giordano, Emanuele Bellacchio, Luigi Bagella and Marco G. Paggi

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Retinoblastoma (RB) family proteins pRb, p107 and pRb2/p130 are important cellular factors which play a well-recognized role as tumor and growth suppressors. These proteins are actively involved in the negative control of the cell cycle and their function is modulated via complex homeostatic processes, most of them involving post-translational regulation of their phosphorylation status. Interestingly, the family members p107 and pRb2/p130 share the ability to physically interact and inhibit the kinase activity of the Cdk2/Cyclin A and Cdk2/Cyclin E complexes. Regarding pRb2/p130, its inhibitory effect on the Cdk2/Cyclin A activity has been attributed to the “spacer” region. Recently, a 39 aa-long pRb2/p130 spacer-derived peptide (Spa310, aa 641-679) has been selected as the sequence responsible for Cdk2/Cyclin A inhibition. Following the identification of this active sequence, here we propose a computer-generated three-dimensional model of the interaction between the Cdk2/Cyclin A complex and the N-terminal 9-amino acid sequence of the Spa310 peptide. We believe this model as useful for the rational development of peptide or peptidomimetic kinase inhibitors to be used for the negative modulation of cell cycle in cancer cells.

Authors

Antonio Giordano

Sbarro Institute for Cancer Research and Molecular Medicine, Philadelphia PA, USA

Emanuele Bellacchio

CSS-Mendel Institute; Rome, Italy

Luigi Bagella

Sbarro Health Research Organization; Temple University; Philadelphia, PA

Marco G. Paggi

Regina Elena Cancer Institute; Rome, Italy

Purchase article for $19

Subscribe to this journal for $129/year