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Molecular motions of human cyclin-dependent kinase 2.
CP. Barrett, ME. Noble
J. Biol. Chem. 2005 Apr;280(14):13993-4005.
PubMed: 15695825
Abstract
We present a comprehensive description of the dynamic behavior of CDK2 in complex with cyclin A, arrived at by analysis of a total of 0.25 micros of solvated molecular dynamics trajectories and 42 deposited CDK2 structures, and refined using other protein simulation algorithms. The CDK2-cyclin A dimer is a dynamic complex of 6 subdomains. Thermal motions are dominated by a relative twisting of the two monomers. The predominant motion within CDK2 is a "breathing" of the N-terminal and C-terminal lobes. The N-terminal lobe of cyclin A is tightly linked to the "PSTAIRE" helix of CDK2 to provide a rigid nucleus to the complex. By contrast, the "CDK-insert" region (residues 219-251) sometimes becomes highly mobile, a behavior that is observed in crystallographic analyses of CDK2 structures and that may relate to its role in recognizing diverse binding partners. We find that the three arginines that anchor phosphothreonine 160 of fully active CDK2 do not contribute equally to structural stabilization. This observation is supported by a survey of protein kinase sequences. We have also explored the physical basis of the role of the phosphate moiety in signaling by artificially modifying the charge of phosphothreonine 160 in molecular dynamics simulations. We find that phosphothreonine binding involves an active process of attraction in which both the receptor site (the arginine triad), and the phosphothreonine have a higher charge than is required to maintain an active conformation once formed. We have deposited our dynamics data to aid protein kinase inhibitor design.
Associated compounds:
Compound Name
with link to compound page |
Structure | Number of references |
---|---|---|
Adenosine triphosphate | 134 |