title: Identification of an hexapeptide that binds to a surface pocket in cyclin A and inhibits the catalytic activity of the complex cyclin-dependent kinase 2-cyclin A.
abstract: The protein-protein complexes formed between different cyclins and cyclin-dependent kinases (CDKs) are central to cell cycle regulation. These complexes represent interesting points of chemical intervention for the development of antineoplastic molecules. Here we describe the identification of an all d-amino acid hexapeptide, termed NBI1, that inhibits the kinase activity of the cyclin-dependent kinase 2 (cdk2)-cyclin A complex through selective binding to cyclin A. The mechanism of inhibition is non-competitive for ATP and non-competitive for protein substrates. In contrast to the existing CDKs peptide inhibitors, the hexapeptide NBI1 interferes with the formation of the cdk2-cyclin A complex. Furthermore, a cell-permeable derivative of NBI1 induces apoptosis and inhibits proliferation of tumor cell lines. Thus, the NBI1-binding site on cyclin A may represent a new target site for the selective inhibition of activity cdk2-cyclin A complex.
authors.affiliation: Departament de Biologia Cellular i Anatomia Patològica, Facultat de Medicina, University of Barcelona, E-08036 Barcelona, Spain.
authors.forename: Núria
authors.initials: N
authors.lastname: Canela
authors.forename: Mar
authors.initials: M
authors.lastname: Orzáez
authors.forename: Raquel
authors.initials: R
authors.lastname: Fucho
authors.forename: Francesca
authors.initials: F
authors.lastname: Mateo
authors.forename: Ricardo
authors.initials: R
authors.lastname: Gutierrez
authors.forename: Antonio
authors.initials: A
authors.lastname: Pineda-Lucena
authors.forename: Oriol
authors.initials: O
authors.lastname: Bachs
authors.forename: Enrique
authors.initials: E
authors.lastname: Pérez-Payá
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D002384:Catalysis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019925:Cyclin A / Q000737:chemistry*; D051357:Cyclin-Dependent Kinase 2 / Q000737:chemistry*; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System; D019151:Peptide Library; D010455:Peptides / Q000737:chemistry*; D010539:Permeability; D011485:Protein Binding
chemical_list: D000970:Antineoplastic Agents; D019925:Cyclin A; D019151:Peptide Library; D010455:Peptides; D000255:Adenosine Triphosphate; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases