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 kinase activity. The crystal structure of the phosphorylated CDK2-CyclinA-ATP gamma S complex has been determined at 2.6 A 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 arginines help extend the influence of the phosphate group through a network of hydrogen bonds to both CDK2 and cyclinA. Comparison with the unphosphorylated CDK2-CyclinA complex shows that the T-loop moves by as much as 7 A, and this affects the putative substrate binding site as well as resulting in additional CDK2-CyclinA contacts. The phosphate group thus acts as a major organizing centre in the CDK2-CyclinA complex.
Russo
A A
AA
Cellular Biochemistry and Biophysics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Jeffrey
P D
PD
Pavletich
N P
NP
D000255:Adenosine Triphosphate / Q000031:analogs & derivatives* / Q000737:chemistry; D042846:CDC2-CDC28 Kinases; D017124:Conserved Sequence; D003461:Crystallography; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases / Q000737:chemistry*; D016213:Cyclins / Q000737:chemistry*; D004789:Enzyme Activation; D008958:Models, Molecular; D010750:Phosphoproteins / Q000737:chemistry*; D010766:Phosphorylation; D011487:Protein Conformation; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry*
D016213:Cyclins; D010750:Phosphoproteins; C022571:adenosine 5'-O-(3-thiotriphosphate); D000255:Adenosine Triphosphate; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases