STRUCTURAL BASIS OF CYCLIN-DEPENDENT KINASE ACTIVATION BY PHOSPHORYLATION

Cyclin-dependent kinase (CDK)-cyclin complexes require phosphorylation on the CDK subunit for full activation of their Ser/Thr protein kinas e activity. The crystal structure of the phosphorylated CDK2-CyclinA-A TP gamma S complex has been determined at 2.6 Angstrom resolution. The phosphate group, which is on the regulatory T-loop of CDK2, is mostly buried, its charge being neutralized by three Arg side chains. The ar ginines help extend the influence of the phosphate group through a net work of hydrogen bonds to both CDK2 and cyclinA. Comparison with the u nphosphorylated CDK2-CyclinA complex shows that the T-loop moves by as much as 7 Angstrom, and this affects the putative substrate binding s ite as well as resulting in additional CDK2-CyclinA contacts. The phos phate group thus acts as a major organizing centre in the CDK2-CyclinA complex.