The Mechanism of Inhibition of the Cyclin-Dependent Kinase-2 as Revealed by the Molecular Dynamics Study on the Complex CDK2 with the Peptide Substrate HHASPRK
| Authors | |
|---|---|
| Year of publication | 2005 |
| Type | Article in Periodical |
| Magazine / Source | Protein Science |
| MU Faculty or unit | |
| Citation | |
| Field | Physical chemistry and theoretical chemistry |
| Keywords | cell cycle; CDK inhibition; phosphorylated tyrosine and threonine; glycine?rich loop; GxGxxG motif |
| Description | Molecular dynamics (MD) simulations were used to explain structural details of cyclin-dependent kinase-2 (CDK2) inhibition by phosphorylation at T14 and/or Y15 located in the glycine-rich loop (G-loop). Tennanosecond- long simulations of fully active CDK2 in a complex with a short peptide (HHASPRK) substrate and of CDK2 inhibited by phosphorylation of T14 and/or Y15 were produced. The inhibitory phosphorylations at T14 and/or Y15 show namely an ATP misalignment and a G-loop shift (5 A) causing the opening of the substrate binding box. The biological functions of the G-loop and GxGxxG motif evolutionary conservation in protein kinases are discussed. The position of the ATP -phosphate relative to the phosphorylation site (S/T) of the peptide substrate in the active CDK2 is described and compared with inhibited forms of CDK2. The MD results clearly provide an explanation previously not known as to why a basic residue (R/K) is preferred at the P2 position in phosphorylated S/T peptide substrates. |
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