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J. Biol. Chem., Vol. 281, Issue 47, 35942-35953, November 24, 2006

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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^*

Núria Canela, Mar Orzáez, Raquel Fucho, Francesca Mateo, Ricardo Gutierrez^¶, Antonio Pineda-Lucena, Oriol Bachs¹, and Enrique Pérez-Payá^||2

From the Departament de Biologia Cellular i Anatomia Patològica, Facultat de Medicina, University of Barcelona, E-08036 Barcelona, Spain, the Departamento de Química Médica, Centro de Investigación Príncipe Felipe, E-46013 Valencia, the ^¶Unitat de Recerca Farmacològica, Institut Municipal d'Investigació Mèdica (IMIM), Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra (UPF), E-08003 Barcelona, and the ^||Instituto de Biomedicina de Valencia, CSIC, E-46010 Valencia, Spain

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.

Received for publication, April 12, 2006 , and in revised form, September 15, 2006.

^* This work was supported by Merck Farma y Química, S.A. and Spanish Ministry of Science and Education Grants (MEC) SAF2001-2811 and BIO2004-998, Fundación Areces, and Centro de Investigación Príncipe Felipe. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence may be addressed: Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, c/Casanova, 143 E-08036 Barcelona, Spain. Tel.: 34-934035286; E-mail: obachs{at}ub.edu. ² To whom correspondence may be addressed: Avda. Autopista del Saler, 16, E-46013 Valencia, Spain. Tel.: 34-963289680; E-mail: eperez{at}cipf.es.

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