Activation and Inhibition of Cyclin-Dependent Kinase-2 by Phosphorylation; A Molecular Dynamics Study Reveals the Functional Importance of the Glycine-Rich Loop
| Authors | |
|---|---|
| Year of publication | 2004 |
| Type | Article in Periodical |
| Magazine / Source | Protein Science |
| MU Faculty or unit | |
| 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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