A model of the complex between cyclin-dependent kinase 5 and the activation domain of neuronal Cdk5 activator.
Tau protein kinase II (TPKII) is a heterodimer comprising a catalytic cyclin-dependent kinase subunit (Cdk5) and a regulatory protein called neuronal Cdk5 activator (Nck5a). TPKII is somewhat reminiscent, therefore, of the Cdk2-cyclin complex important in cell cycle regulation. In fact, although the amino acid sequence of Nck5a has little similarity to those of cyclins, recent experimental results obtained by site-directed mutagenesis studies have indicated that its activation domain, Nck5a*, may adopt a conformation of the cyclin-fold structure. Based on this structural inference, a 3-dimensional model of the Cdk5-Nck5a*-ATP complex was derived from the X-ray structure of Cdk2-cyclinA-ATP complex. The computed structure for TPKII is fully compatible with experimental data derived from studies of the Cdk5-Nck5a system, and also predicts which amino acid residues might be involved in formation of the Cdk5-Nck5a* interface and ATP binding pocket in TPKII. The computational structure also shows the interactive region of Nck5a* and the T-loop of Cdk5, a critical region in TPKII which functions as a gate-control-lever of the catalytic cleft. Furthermore, a physical mechanism is put forth to explain why the activation of TPKII is not dependent upon phosphorylation of the Cdk5 subunit, a puzzle long-standing in this area. These findings provide a model with which to consider design of compounds which might serve as inhibitors of TPKII.
Chou
K C
KC
Computer-Aided Drug Discovery, Pharmacia & Upjohn, Kalamazoo, Michigan 49007-4940, USA.
Watenpaugh
K D
KD
Heinrikson
R L
RL
D000255:Adenosine Triphosphate / Q000737:chemistry; D000544:Alzheimer Disease / Q000378:metabolism; D000595:Amino Acid Sequence; D001665:Binding Sites; D042846:CDC2-CDC28 Kinases; D051357:Cyclin-Dependent Kinase 2; D051360:Cyclin-Dependent Kinase 5; D018844:Cyclin-Dependent Kinases / Q000737:chemistry*; D019281:Dimerization; D004789:Enzyme Activation; D006801:Humans; D006860:Hydrogen Bonding; D008958:Models, Molecular; D009419:Nerve Tissue Proteins / Q000737:chemistry*; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry*; D017433:Protein Structure, Secondary; D016415:Sequence Alignment; D055672:Static Electricity
D009419:Nerve Tissue Proteins; C089495:neuronal Cdk5 activator (p25-p35); D000255:Adenosine Triphosphate; D051360:Cyclin-Dependent Kinase 5; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; C495905:CDK5 protein, human; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases; C079134:tau protein kinase II