Influences of phosphorylation on Thr14/Tyr15 in CDK5 in the presence of roscovitine/ATP and HHASPRK

Abstract

Binding details of roscovitine, ATP and HHASPRK peptide in complex with both unphosphorylated and phosphorylated cyclin-dependent kinase 5 (CDK5) from molecular dynamics simulations using a crystal structure of CDK2/cyclinA/ATP/HHASPRK and three CDK5/p25/roscovitine systems as references are presented. The influence of phosphorylation on well-conserved amino acids (Thr14 and Tyr15) on the conformation of the inhibition loop (G-loop) is investigated. The simulations suggest that the long ATP phosphate group affects the conformation of the loop differently in different complexes. Binding patterns of ATP in CDK5 are then studied and compared with those in CDK2. The residues on the G-loop affect the conformation of the ATP phosphate group and thus influence the hydrogen bonding network around the ligand. In addition, bindings of the peptide in CDK5 are investigated and compared with that in the crystal structure. Also, the possible conformation of the terminal lysine side chain of the peptide is analysed and suggested.