Canela Núria, Orzáez Mar, Fucho Raquel, Mateo Francesca, Gutierrez Ricardo, Pineda-Lucena Antonio, Bachs Oriol, Pérez-Payá Enrique
Departament de Biologia Cellular i Anatomia Patològica, Facultat de Medicina, University of Barcelona, E-08036 Barcelona, Spain.
J Biol Chem. 2006 Nov 24;281(47):35942-53. doi: 10.1074/jbc.M603511200. Epub 2006 Sep 25.
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.
不同细胞周期蛋白与细胞周期蛋白依赖性激酶（CDK）之间形成的蛋白质-蛋白质复合物是细胞周期调控的核心。这些复合物是开发抗肿瘤分子的化学干预的有趣靶点。在此，我们描述了一种全 d-氨基酸六肽 NBI1 的鉴定，它通过与细胞周期蛋白 A 选择性结合来抑制细胞周期蛋白依赖性激酶 2（cdk2）-细胞周期蛋白 A 复合物的激酶活性。抑制机制对 ATP 是非竞争性的，对蛋白质底物也是非竞争性的。与现有的 CDK 肽抑制剂不同，六肽 NBI1 干扰 cdk2-细胞周期蛋白 A 复合物的形成。此外，NBI1 的细胞可渗透衍生物诱导肿瘤细胞系凋亡并抑制其增殖。因此，细胞周期蛋白 A 上的 NBI1 结合位点可能代表了选择性抑制 cdk2-细胞周期蛋白 A 复合物活性的新靶点。
