1bi7
|
MECHANISM OF G1 CYCLIN DEPENDENT KINASE INHIBITION FROM THE STRUCTURE OF THE CDK6-P16INK4A TUMOR SUPPRESSOR COMPLEX
OverviewOverview
The cyclin-dependent kinases 4 and 6 (Cdk4/6) that control the G1 phase of, the cell cycle and their inhibitor, the p16INK4a tumour suppressor, have a, central role in cell proliferation and in tumorigenesis. The structures of, Cdk6 bound to p16INK4a and to the related p19INK4d reveal that the INK4, inhibitors bind next to the ATP-binding site of the catalytic cleft, opposite where the activating cyclin subunit binds. They prevent cyclin, binding indirectly by causing structural changes that propagate to the, cyclin-binding site. The INK4 inhibitors also distort the kinase catalytic, cleft and interfere with ATP binding, which explains how they can inhibit, the preassembled Cdk4/6-cyclin D complexes as well. Tumour-derived, mutations in INK4a and Cdk4 map to interface contacts, solidifying the, role of CDK binding and inhibition in the tumour suppressor activity of, p16INK4a.
DiseaseDisease
Known diseases associated with this structure: Li Fraumeni syndrome OMIM:[600160], Melanoma and neural system tumor syndrome OMIM:[600160], Melanoma, cutaneous malignant, 2 OMIM:[600160], Orolaryngeal cancer, multiple, OMIM:[600160], Pancreatic cancer/melanoma syndrome OMIM:[600160]
About this StructureAbout this Structure
1BI7 is a Protein complex structure of sequences from Homo sapiens. Full crystallographic information is available from OCA.
ReferenceReference
Structural basis for inhibition of the cyclin-dependent kinase Cdk6 by the tumour suppressor p16INK4a., Russo AA, Tong L, Lee JO, Jeffrey PD, Pavletich NP, Nature. 1998 Sep 17;395(6699):237-43. PMID:9751050
Page seeded by OCA on Mon Nov 12 16:10:09 2007