1G3N

STRUCTURE OF A P18(INK4C)-CDK6-K-CYCLIN TERNARY COMPLEX

Summary for 1G3N

• Entry DOI: 10.2210/pdb1g3n/pdb
• Related: 1BI7 1BI8
• Descriptor: CYCLIN-DEPENDENT KINASE 6, CYCLIN-DEPENDENT KINASE 6 INHIBITOR, V-CYCLIN (3 entities in total)
• Functional Keywords: cyclin-dependent kinase, ink4 inhibitor, viral cyclin, cell cycle, signaling protein
• Biological source: Homo sapiens (human); More
• Cellular location: Cytoplasm: Q00534
• Total number of polymer chains: 6
• Total formula weight: 166461.93

Authors

Jeffrey, P.D.,Tong, L.,Pavletich, N.P. (deposition date: 2000-10-24, release date: 2001-01-10, Last modification date: 2024-02-07)

Primary citation

Jeffrey, P.D.,Tong, L.,Pavletich, N.P.
Structural basis of inhibition of CDK-cyclin complexes by INK4 inhibitors.
Genes Dev., 14:3115-3125, 2000

PubMed Abstract: The cyclin-dependent kinases 4 and 6 (Cdk4/6) that drive progression through the G(1) phase of the cell cycle play a central role in the control of cell proliferation, and CDK deregulation is a frequent event in cancer. Cdk4/6 are regulated by the D-type cyclins, which bind to CDKs and activate the kinase, and by the INK4 family of inhibitors. INK4 proteins can bind both monomeric CDK, preventing its association with a cyclin, and also the CDK-cyclin complex, forming an inactive ternary complex. In vivo, binary INK4-Cdk4/6 complexes are more abundant than ternary INK4-Cdk4/6-cyclinD complexes, and it has been suggested that INK4 binding may lead to the eventual dissociation of the cyclin. Here we present the 2.9-A crystal structure of the inactive ternary complex between Cdk6, the INK4 inhibitor p18(INK4c), and a D-type viral cyclin. The structure reveals that p18(INK4c) inhibits the CDK-cyclin complex by distorting the ATP binding site and misaligning catalytic residues. p18(INK4c) also distorts the cyclin-binding site, with the cyclin remaining bound at an interface that is substantially reduced in size. These observations support the model that INK4 binding weakens the cyclin's affinity for the CDK. This structure also provides insights into the specificity of the D-type cyclins for Cdk4/6.

PubMed: 11124804
DOI: 10.1101/gad.851100

Experimental method

X-RAY DIFFRACTION (2.9 Å)