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Published online before print May 7, 2004, 10.1110/ps.03578504
Protein Science (2004), 13:1449-1457. Published by Cold Spring Harbor Laboratory Press. Copyright © 2004 The Protein Society
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Activation and inhibition of cyclin-dependent kinase-2 by phosphorylation; a molecular dynamics study reveals the functional importance of the glycine-rich loop

Iveta Bártová1, Michal Otyepka2, Zdenek Kríz1 and Jaroslav Koca1

1 National Centre for Biomolecular Research, Faculty of Science, Masaryk University, Brno, Czech Republic
2 Department of Physical Chemistry, Palacky University, Olomouc, Czech Republic

(RECEIVED December 17, 2003; FINAL REVISION February 20, 2004; ACCEPTED February 20, 2004)



Abstract

Nanoseconds long molecular dynamics (MD) trajectories of differently active complexes of human cyclin-dependent kinase 2 (inactive CDK2/ATP, semiactive CDK2/Cyclin A/ATP, fully active pT160-CDK2/Cyclin A/ATP, inhibited pT14-; pY15-; and pT14,pY15,pT160-CDK2/Cyclin A/ATP) were compared. The MD simulations results of CDK2 inhibition by phosphorylation at T14 and/or Y15 sites provide insight into the structural aspects of CDK2 deactivation. The inhibitory sites are localized in the glycine-rich loop (G-loop) positioned opposite the activation T-loop. Phosphorylation of T14 and both inhibitory sites T14 and Y15 together causes ATP misalignment for phosphorylation and G-loop conformational change. This conformational change leads to the opening of the CDK2 substrate binding box. The phosphorylated Y15 residue negatively affects substrate binding or its correct alignment for ATP terminal phospho-group transfer to the CDK2 substrate. The MD simulations of the CDK2 activation process provide results in agreement with previous X-ray data.

Keywords: cell cycle; CDK regulation; phosphorylated tyrosine; threonine

Reprint requests to: Michal Otyepka, Department of Physical Chemistry, Palacky University, tr. Svobody 26, 771 46 Olomouc, Czech Republic; e-mail: otyepka{at}aix.upol.cz, fax: 420-585634420; or Jaroslav Koca, National Centre for Biomolecular Research, Faculty of Science, Masaryk University, Kotlárská 2, 611 37 Brno, Czech Republic; e-mail: jkoca{at}chemi.muni.cz; fax: 420-541129506.

Dedicated to Professor Milan Kratochvíl on the occasion of his 80th birthday.

Article published online ahead of print. Article and publication date are at http://www.proteinscience.org/cgi/doi/10.1110/ps.03578504.


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