Activation and Inhibition of Cyclin-Dependent Kinase-2 by Phosphorylation; A Molecular Dynamics Study Reveals the Functional Importance of the Glycine-Rich Loop

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Authors

BÁRTOVÁ Iveta OTYEPKA Michal KŘÍŽ Zdeněk KOČA Jaroslav

Year of publication 2004
Type Article in Periodical
Magazine / Source Protein Science
MU Faculty or unit

Faculty of Science

Citation
Field Physical chemistry and theoretical chemistry
Keywords cell cycle; CDK regulation; phosphorylated tyrosine; threonine
Description Nanoseconds long molecular dynamics (MD) trajectories of differently active complexes of human cyclin-dependent kinase 2 (inactive CDK2/ATP, semi-active CDK2/Cyclin A/ATP, fully-active pT160-CDK2/Cyclin A/ATP, inhibited pT14-; pY15-; and pT14,pY15,pT160-CDK2/Cyclin A/ATP) are compared. The MD simulations results of CDK2 inhibition by phosphorylation at T14 and/or Y15 sites provide insight into 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.
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