A Molecular Dynamics Study of the Cyclin-Dependent Kinase-2 (CDK2) with Substrate Peptide (HHASPRK), Inhibition of CDK2 by Phosphorylation
| Authors | |
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| Year of publication | 2004 |
| Type | Article in Proceedings |
| Conference | Materials in Structure Chemistry, Biology, Physics and Technology |
| MU Faculty or unit | |
| Citation | |
| Web | http://www.xray.cz/setkani |
| Field | Physical chemistry and theoretical chemistry |
| Keywords | Cyclin dependent kinase; inhibition; phosphorylation; molecular dynamics |
| Description | The cyclin-dependent kinase, CDK2, regulates the eukaryotic cell cycle at the G1; S boundary. CDKs activity is regulated by complex mechanism including binding to positive regulatory subunit and phosphorylation at positive and/or negative regulatory sites [1]. For activation CDK2 requires binding to Cyclin A or Cyclin E. The CDK2 obtains full activity after phosphorylation of the threonine residue (T160) in the activation segment (T-loop) [2]. CDK2 catalyzes the phosphoryl transfer of the adenosine-5-triphosphate (ATP) g-phosphate to serine or threonine hydroxyl in the protein substrate. The CDKs activity is inhibited in several ways, for example, by (de)phosphorylation, interaction with various natural protein inhibitors [3,4], etc. The CDK2 can be negatively regulated by phosphorylation at Y15 and, to a lesser extent, at T14 in the glycine-rich loop (G-loop) [5]. This work describes behavior of the fully active CDK2 (pT160-CDK2/Cyclin A/ATP complex) with substrate peptide (HHASPRK) and CDK2 inhibited by phosphorylation at T14, Y15, and T14/Y15 residues altogether in the G-loop using molecular dynamics simulations with the Cornell et al. force field as implemented in the AMBER software package [6]. Inhibited complexes of CDK2 were prepared from pT160-CDK2/Cyclin A/HHASPRK/ATP (1QMZ PDB ID code) by phosphorylation of the T14 and/or Y15 residues. Enzyme dynamics was studied during 8 ns long trajectory. Differences in conformational behavior of key residues for substrate binding and phosphoryl transfer of fully active vs. inhibited CDK2 will be presented. |
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