Interaction between the Cdk2/cyclin A complex and a small molecule derived from the pRb2/p130 spacer domain: a theoretical model.
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 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) was 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 nine-amino acid sequence of the Spa310 peptide. We believe this model to be useful for the rational development of peptide or peptidomimetic kinase inhibitors for negative cell cycle modulation in cancer cells.
Giordano
Antonio
A
Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, Temple University, Philadelphia, Pennsylvania 19122, USA. giordano@temple.edu
Bellacchio
Emanuele
E
Bagella
Luigi
L
Paggi
Marco G
MG
D000595:Amino Acid Sequence; D001665:Binding Sites / Q000235:genetics; D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism*; D003198:Computer Simulation; D019925:Cyclin A / Q000737:chemistry / Q000378:metabolism*; D051357:Cyclin-Dependent Kinase 2 / Q000737:chemistry / Q000378:metabolism*; D021901:DNA, Intergenic / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary / Q000235:genetics; D056485:Retinoblastoma-Binding Protein 2; D050717:Retinoblastoma-Like Protein p130 / Q000737:chemistry / Q000378:metabolism*
D002352:Carrier Proteins; D019925:Cyclin A; D021901:DNA, Intergenic; D050717:Retinoblastoma-Like Protein p130; C070050:KDM5A protein, human; D056485:Retinoblastoma-Binding Protein 2; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2