Mechanisms of cyclin-dependent kinase regulation: structures of Cdks, their cyclin activators, and Cip and INK4 inhibitors.
The cyclin-dependent kinases (Cdks) have a central role in coordinating the eukaryotic cell division cycle, and also serve to integrate diverse growth-regulatory signals. Cdks are controlled through several different processes involving the binding of activating cyclin subunits, of inhibitory Cip or INK4 subunits, and phosphorylation. Crystallographic studies of Cdks in four different complexes, reviewed here, have revealed the mechanisms by which these regulatory processes control the Cdk switches. All of these mechanisms involve conformational changes in and around the catalytic cleft of the kinase, indicating that Cdks have evolved an intrinsic conformational flexibility. This flexibility is central to their ability to switch states in response to a diverse range of growth-regulatory signals.
Pavletich
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Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
D000818:Animals; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018844:Cyclin-Dependent Kinases / Q000737:chemistry* / Q000378:metabolism*; D016213:Cyclins / Q000737:chemistry / Q000378:metabolism*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D010766:Phosphorylation; D011487:Protein Conformation
C493956:CDKN1A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; D018844:Cyclin-Dependent Kinases